EA044109B1 - PYRAZOLOPYRIDINE DERIVATIVES WITH GLP-1 RECEPTOR AGONIST EFFECT - Google Patents

Description

Field of technology

This invention relates to a GLP-1 receptor agonist compound having the same effect as GLP-1, a salt or solvate thereof, or a compound or a salt of said compound. This invention also relates to a prophylactic agent or drug for non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity containing such a compound, salt or solvate as an active ingredient.

State of the art

Glucagon-like peptide-1 (GLP-1) is an incretin secreted by L cells in the small intestine as nutrients pass through the digestive tract, and GLP-1 is known to exhibit a wide range of effects through modulation of the GLP-1 receptor, such as stimulating glucose-dependent insulin secretion, inhibition of glucagon secretion, delayed gastric emptying, appetite suppression. Although GLP-1 analogue is already commercially available as a drug for the treatment of diabetes and is considered one of the most effective drugs for the treatment of diabetes due to its potent effect in reducing HbA1c levels and weight loss, its use requires invasive subcutaneous administration. Thus, the development of a GLP-1 receptor agonist that can be administered non-invasively is an urgent task. Previous attempts have been made to improve the bioavailability during oral administration of a GLP-1 analogue: for example, semaglutide through the absorption enhancer (N-(8-(2hydroxybenzoyl)amine)sodium caprylate: SNAC) (Patent 1) and through the development of a small molecule GLP-1 receptor agonist (patents 2 and 3), but still requires further improvement in the properties of the drug, including activity, metabolic stability and bioavailability. The next two compounds from Chemotheca are known as 2-[(2,4,6,7-tetrahydro-5H-pyrazolo[4,3c]pyridin-5-yl)carbonyl]-1H-indole.

Formula 1

RN 1638421-28-9 RM 1269202-37-0

In addition, Patent 4 describes the following pyrazolopyridine derivative as a compound that is useful in the prevention/therapy of sleeping sickness, leishmaniasis or the like caused by a eukaryote such as the Blastocrithidia parasite (eg, Trypanosomatidae).

Chemical formula 2

References patent literature

Patent 1: WO 2012/080471.

Patent 2: WO 2009/111700.

Patent 3: WO 2010/114824.

Patent 4: WO 2016/038045.

The essence of the invention and the technical problem

The object of the present invention is to provide a compound that is a GLP-1 receptor agonist having the same effect as a GLP-1 peptide, which can be administered non-invasively and which has improved potency, metabolic stability and bioavailability, its a salt or solvate of either a compound or salts of a compound, and also propose a prophylactic or medicinal product for non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity containing such a compound, salt or solvate as an active ingredient.

- 1 044109

The solution of the problem

The inventors of the present invention carefully studied the above problem in order to solve it, and found that the compound represented by the formula

in which the indole ring and the pyrazolopyridine moiety are linked to each other through a substituent, has the same effect as GLP-1 peptide as a GLP-1 receptor agonist, and thus provides a solution to the object of the present invention.

In other words, the invention described below is one aspect of the present invention.

The compound represented by the formula

Salt or solvate of a compound of the formula

A compound wherein the compound is 3-[(1S,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2[(4S)-2-(4-fluoro-3 ,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4oxadiazol-5-one.

A compound wherein the compound is a pharmaceutically acceptable salt of 3-[(1S,2S)-1[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4 ,3-c]pyridin-5-carbonyl]indol-1-yl]-2methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one.

Compound of the following formula:

- 2 044109

A salt of a compound with the following formula:

Solvate of a compound with the following formula:

Hemicalcium salt hydrate of the compound formula:

Hemicalcium salt hydrate of the compound formula:

A pharmaceutical composition containing any of the above compounds, its salt or solvate or compounds or salts of a compound as an active substance and an excipient.

A pharmaceutical composition containing a salt of any of the above compounds as an active ingredient and an excipient.

A pharmaceutical composition containing a solvate of any of the above compounds as an active ingredient and an excipient.

A pharmaceutical composition containing a salt solvate of any of the above compounds as an active ingredient and an excipient.

- 3 044109

A method of treating non-insulin-dependent diabetes mellitus (type 2 diabetes) in a patient in need thereof, the method comprising administering an effective amount of the above compound, a salt or solvate thereof, or a salt of the above compound.

A method for preventing non-insulin-dependent diabetes mellitus (type 2 diabetes) in a patient in need thereof, the method comprising administering an effective amount of the above compound, a salt or solvate thereof, or a salt of the above compound.

A method of treating obesity in a patient in need thereof, the method comprising administering an effective amount of the above compound, a salt or solvate thereof, or a salt of the above compound.

A method for preventing obesity in a patient in need thereof, the method comprising administering an effective amount of the above compound, a salt or solvate thereof, or a salt of the above compound.

Beneficial effects of the invention

The compound, a salt or solvate thereof of either a compound or a salt of a compound, of this invention has an effect similar to GLP-1 peptide as a GLP-1 receptor agonist and is a non-peptide agent for the prevention or treatment of non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity, which is expected to provide sufficient oral bioavailability.

Brief description of graphic materials

In fig. 1 shows the result of powder X-ray diffractometry measurement of the sodium salt hydrate crystal of compound 1 obtained in Example 163 (sample 160a). The vertical axis indicates the diffraction intensity, and the horizontal axis indicates the diffraction angle 2θ (°).

In fig. 2 shows the result of powder X-ray diffractometry measurement of the sodium salt hydrate crystal of compound 1 obtained in Example 163 (sample 160b). The vertical axis indicates the diffraction intensity, and the horizontal axis indicates the diffraction angle 2θ (°).

In fig. 3 depicts a powder X-ray diffractometry measurement of a hydrate crystal of exemplary compound 66 obtained in Example 163 (Sample 161a). The vertical axis indicates the diffraction intensity, and the horizontal axis indicates the diffraction angle 2θ (°).

In fig. 4 depicts an X-ray powder diffraction measurement of a crystal of exemplary compound 66 prepared in Example 163 (Sample 161b). The vertical axis indicates the diffraction intensity, and the horizontal axis indicates the diffraction angle 2θ (°).

In fig. 5 shows a powder X-ray diffraction measurement result of a calcium salt hydrate crystal of exemplary compound 67 obtained in Example 163 (Sample 162a). The vertical axis indicates the diffraction intensity, and the horizontal axis indicates the diffraction angle 2θ (°).

In fig. 6 shows a powder X-ray diffraction measurement result of a calcium salt hydrate crystal of exemplary compound 67 obtained in Example 163 (Sample 162b). The vertical axis indicates the diffraction intensity, and the horizontal axis indicates the diffraction angle 2θ (°).

In fig. 7 shows the result of thermogravimetry/differential thermal analysis of the sodium salt hydrate crystal of compound 1 obtained in Example 164. The horizontal axis indicates the temperature (°C), and the right vertical axis indicates the change in mass (%) of the sample during thermogravimetry. The left vertical axis indicates the heat flux observed in the differential thermal analysis.

In fig. 8 shows the result of thermogravimetry/differential thermal analysis of the calcium salt hydrate crystal of the compound of Example 67 obtained in Example 164. The horizontal axis indicates the temperature (°C), and the right vertical axis indicates the change in mass (%) of the sample during thermogravimetry. The left vertical axis indicates the heat flux observed in the differential thermal analysis.

In fig. 9 depicts the effect of Example 67 and exenatide on insulin secretion following intravenous glucose administration to male cynomolgus monkeys. The area under the insulin curve is expressed as mean ± standard error (n=6). Each pharmaceutical was administered in a crossover study. * indicates that the group value has a statistically significant difference when compared with the vehicle group at P < 0.025, and ** indicates that the group value has a statistically significant difference when compared with the vehicle group at P < 0.005 (Williams test). The concentration of each drug is the average of the measured plasma drug concentration.

In fig. 10 depicts the effect of Example 67 and exenatide on plasma glucose levels following intravenous glucose administration to male cynomolgus monkeys. The area under the glucose curve is expressed as mean ± standard error (n=6). Each pharmaceutical was administered in a crossover study. * indicates that the group value has a statistically significant difference when compared with the vehicle group at P < 0.025, and ** indicates that the group value has a statistically significant difference when compared with the vehicle group at P < 0.005 (Williams test).

- 4 044109

The concentration of each drug is the average of the measured plasma drug concentration.

In fig. 11 depicts the effect of Example 67 and exenatide on appetite in male cynomolgus monkeys. Food intake is presented by mean ± standard error (n=6). Each pharmaceutical was administered in a crossover study. * indicates that the group value has a statistically significant difference when compared with the vehicle group at P < 0.025, and ** indicates that the group value has a statistically significant difference when compared with the vehicle group at P < 0.005 (Williams test).

In fig. 12 depicts the time profile of drug plasma concentrations following oral administration of the drug to male cynomolgus monkeys. Plasma concentrations are expressed as mean n=2 values for each dose.

Description of Embodiments of the Present Invention

The present invention is further described below and is not limited to the present description. Definitions.

The term halogen atom, as used herein, means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like. Halogen atoms that are preferred as the aryl substituent in the present invention (eg, R ^a when X in formula (I) is -CR ^a =) are a fluorine atom and a chlorine atom. The halogen atoms that are preferred as the alkyl substituent in the present invention (eg, the C1.6αalkyl substituent when the C6_10aryl, or 5-10 membered heteroaryl Q ¹ is substituted with a _C1.6 alkyl) are a fluorine atom and a chlorine atom. Specific examples C ₁ . ₆ alkylα having a halogen atom as a substituent include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, pentafluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, heptafluoropropyl, 3,3,3 trifluoropropyl, 2,3-dichloropropyl, 1 -fluoro-3bromopropyl, 4-bromobutyl, 3,3,3,4,4-pentafluorobutyl, 4,4-dichlorobutyl, 5-iodopentyl, 5,5-difluoropentyl, 6-chlorhexyl and 6,6,6-trifluorohexyl.

Term C ₁ . ₆ alkyl, as used herein, is a straight or branched chain alkyl group containing from 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl and 2-ethylbutyl.

Term C ₁ . ₆ alkoxy, as used herein, means the group: C ₁ . ₆ alkyl-O group, in which C ₁ . ₆ alkyl has already been defined. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobuoxy, sec-butoxy, tert-butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy and 2ethylbutoxy.

The term (C ₁ . ₆ alkyl) carbonyl as used herein means a group: (Cl . ₆ α alkyl)-C(O)-group in which C ₁ . ₆ alkyl has already been defined. Examples include methylcarbonyl (acetyl), ethylcarbonyl (propionyl), n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, 1-methylpropylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, 2-methylcarbonyl, 1, 1-dimethylpropylcarbonyl, 1-ethylpropylcarbonyl, ngexylcarbonyl, 4-methylpentylcarbonyl and 2-ethylbutylcarbonyl.

The term C _{6_10} aryl as used herein means an aromatic carbocyclic group, and it may contain a non-aromatic moiety in addition to an aromatic _moiety . The ring may be monocyclic or may be a bicyclic aryl that is fused to a benzene ring or a monocyclic aryl ring. Examples include phenyl, 1-naphthyl, 2-naphthyl, azulenyl, isochromanyl, 2,4-dihydro-N-isoquinolin-3-onyl, and 1,3-dihydrobenzimidazol-2-onyl. A preferred example is phenyl. The term heteroaryl as used herein means an aromatic 5-10 membered cyclic group which includes, among the ring-forming atoms, one or more heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and it may contain a non-aromatic moiety in addition to the aromatic part. The ring may be monocyclic or may be a bicyclic heteroaryl that is fused to a benzene ring or a monocyclic heteroaryl ring. Examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzo oxazolyl, benzooxadiazolyl, benzoimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl, benzoisoxazolyl and benzoisothiazolyl. The term heterocyclyl, as used herein, means a non-aromatic cyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms, and may be fully saturated or partially unsaturated. The ring may be a monocyclic ring, a bicyclic ring or a spiro ring, from 3 to 12 members, preferably from 3 to 10 members. Examples include oxetanyl, azetidinyl, 3,7-dioxa-9azabicyclo[3,3,1]nonanyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,

- 5 044109 tetrahydropyranyl, tetrahydrofuranyl, 2-oxa-6-azaspiro[3,3]heptyl, 2-azaspiro[3,3]heptyl, 2,6diazaspiro[3,3]heptyl, 2-thia-6-azaspiro[3 ,3]heptyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, thianyl, oxanyl, thioxanyl, indolinyl, isoindolinyl, tetrahydroindolinyl, quinucledinyl, azepinyl and tropanil.

Term C ₃ . ₁₅ cycloalkyl, as used herein, means a monovalent group obtained by the removal of any one hydrogen atom from a cyclic saturated aliphatic hydrocarbon containing from 3 to 15 carbon atoms. In addition, the term C _3-8 cycloalkyl means a cycloalkyl containing from three to eight carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In addition, the term C _3-6 cycloalkyl means a cycloalkyl containing from 3 to 6 carbon atoms. When two groups together form a C _3-15 cycloalkane ring, the resulting group is divalent. Examples include cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, cycloheptane-1,1-diyl and cyclooctane-1,1-diyl. When two groups are connected at two carbon atoms to form a C _3-8 carbocyclic ring, the resulting ring forms a fused ring. Examples include ring structures in which two carbon atoms are linked via -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ - and -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -.

In addition, a cycloalkane ring, a carbocyclic ring, a cyclic hydrocarbon, in a cycloalkyl may be a bridged ring. Examples of bridged rings in C _3-15 cycloalkyl include bicyclo[1,1,0]butane, bicyclo[3,2,1]octane, bicyclo[5,2,0]nonane, bicyclo[4,3,2]undecane, tricyclo[2,2,1,0 ^2,6 ]heptane, tricyclo[4,3,1,1 ^2,5 ]undecane, tricyclo[3,3,1,1 ^3,7 ]decane (adamantane), tricyclo[ 3,3,1,1 ^3,7 ]decane-2-ylidene (2-adamantylidene), pentacyclo[4,2,0,0 ^2,5 0 ^3,8, 0 ^4,7 ] octane (cubane), and examples of C _3-15 cycloalkyl include bicyclo[1,1,0]butyl, bicyclo[3,2,1]octyl, bicyclo[5,2,0]nonyl, bicyclo[4,3,2]undecyl, tricyclo[2 ,2,1,0 ^2,6 ]heptyl, tricyclo[4,3,1,1 ^2,5 ]undecyl, adamantyl, 2-adamantydenyl and cubanyl.

This invention relates to the compound represented by formula (I), a pharmaceutically acceptable salt or solvate thereof, or a compound or a salt of a compound.

Chemical formula 8

X represents -N= or -CR ^a =; R ^a is selected from hydrogen atom, halogen atom and Aralkyl. X is preferably -N=, -CH= or -CF=, more preferably -CH=.

Y is selected from -C(=O)-, -CHR- and -S(=O) ₂ -; R represents a hydrogen atom or C _1-6 alkyl.

Q ¹ is C6-10 aryl or 5-10 membered heteroaryl, wherein C6-10 aryl and 5-10 member heteroaryl are optionally substituted with one to five substituents independently selected from a halogen atom, C1-6alkyl (wherein C1-6αalkyl is optionally substituted with one or more halogen atoms) and C1-6 alkoxy. Q ¹ is preferably phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with one to four substituents independently selected from halogen and C1-6 alkyl. More preferably, Q ¹ is phenyl substituted with two to three substituents independently selected from halogen and C _1-6 αlkyl.

Q ² is a 3-12 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 3-12 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one to three substituents independently selected from a halogen atom, C1-6alkyl (where C1-6alkyl is optionally substituted with one or more halogen atoms), C1-6alkoxy and -NR ^Qa R ^Qb , and two C1-6alkyl groups together with the carbon atom to which they are attached may form a _C3-8 carbocyclic ring; and R ^Qa and R ^Qb are independently selected from hydrogen, C1-6alkyl and (C1-6alkyl)carbonyl. Preferably, Q ² is i) a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is optionally substituted with one or more Aralkyls, and the two Aralkyl groups together with the carbon atom to which they are attached may form a C3-8 carbocyclic ring, or ii) a 5- 6-membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy and -NR ^Qc R ^{Qd and R Qc and} R ^Qd are independently selected from a hydrogen atom and a C1-6 alkyl. Preferably, Q ² is a 5-6 membered heterocyclyl or heteroaryl, wherein the 5-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one to three C1-6 alkyls.

^R1 , ^R2 and ^R3 are each independently selected from hydrogen and A-6alkyl (wherein A-6alkyl is optionally substituted with one or more substituents independently selected from halogen, C1-6alkoxy and hydroxy). Preferably, the combination of R ¹ , R ² and R ³ is selected from: all hydrogen atoms; R ¹ represents a hydrogen atom, R ² represents a hydrogen atom and R ³ represents C1-6alkyl; and R ¹

- 6 044109 represents a hydrogen atom, R ² represents C1-6alkyl and R ³ represents C1-6alkyl.

R ⁴ , R ⁵ and R 6 are independently selected from hydrogen atom, halogen atom and C _1-6 alkyl. Preferably, R ⁴ , R ⁵ and R ⁶ independently represent a hydrogen atom or a fluorine atom. More preferably, the combinations of R ⁴ , R ⁵ and R ⁶ are: all hydrogen atoms; or R ⁴ represents a hydrogen atom, R ⁵ represents a hydrogen atom and R ⁶ represents a fluorine atom.

R ⁷ and R ⁸ independently represent a hydrogen atom or a C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from a halogen atom and a C3-15 cycloalkyl, or R ⁷ and R ⁸ together with the carbon atom to which they attached, may form a C3-15 cycloalkane ring, wherein the C _3-15 cycloalkane ring formed by the combination of R ⁷ and R ⁸ is optionally substituted with one to three C1-6 alkyls, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from a halogen atom , hydroxy, -NR ^7a R ^7b , C1-6αalkoxy and 3-12 membered heterocyclyl, and R ^7a and R ^7b are independently selected from hydrogen, C1-6alkyl and (C1-6alkyl)carbonyl. Preferably, R ⁷ and R ⁸ together with the carbon atom to which they are attached form a C 3-8 cycloalkane ring, wherein the C _3-8 cycloalkyl so formed is optionally substituted with one or more C _1-6 alkyls, wherein the C _1-6 alkyl is optionally substituted with one or more hydroxy. C _3-8 cycloalkyl is preferably C _3-6 cycloalkyl. A preferred C _3-6 cycloalkyl is, for example, cyclopentyl.

n1 is equal to an integer from 0 to 3; n2 is an integer from 0 to 5. n1 and n2 are each preferably 0 to 2, more preferably 0 to 1, and even more preferably 0. Also, the combination of n1 and n2 is preferably 0 and 0, 0 and 1, 0 and 2, 1 and 0, 1 and 1, 2 and 0, more preferably 0 and 0, 0 and 1, 1 and 0, 2 and 0, and even more preferably 0 and 0.

R ⁹ is selected from the group represented by formulas (IIa), (IIb), (IIc), (IId).

Chemical formula 9 ι « Ii h JLд

N '''''NR ⁴ 'N'NR'N' ^: 'NR^·

N=N 0—'—A

IM Ο 11 lb; R·' (Ik; ι Ά (|Ш

-CO ₂ R ^9f and -C(=O)-NR ^9g R ^9h ; and each ^R9a , ^R9b , ^R9c , ^R9d and ^R9g is independently selected from hydrogen, C1-6alkyl (wherein C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen and C1-6alkoxy) and (C1 -6alkyl)carbonyl; R ^9e represents a hydrogen atom or C1-6alkyl which is optionally substituted with one or more substituents independently selected from a halogen atom; R ^9f represents a hydrogen atom or C1-6alkyl, R ^9h represents a hydrogen atom, C1-6alkyl, ( _C1-6 alkyl)carbonyl, cyano or -S(=O) _n3 -R ⁹ⁱ ; n3 is an integer from 0 to 2, and R ⁹ⁱ is C _1-6 alkyl.

Z ¹ is selected from the group represented by formulas (IIIa), (IIIb), (IIIc), (IIId) and (IIIe).

Chemical formula 10

where R ^za is selected from hydrogen, aralkyl and (C1-6alkyl)carbonyl, R ^zb and R ^zc are independently hydrogen or C1-6alkyl, n4 is an integer from 1 to 3, n5 and n6 are independently an integer from 0 to 10.

* indicates the binding position to the pyrazolopyridine structure, ** indicates the binding position to Z ² .

Z ² is selected from L^alkyl, C _3-15 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, where C _3-15 cycloalkyl, 3-12 membered heterocyclyl, C _{6 -10} aryl and 5-10 membered heteroaryl are optionally substituted with one to five substituents independently selected from group A.

Group A:

a) oxo,

b) halogen atom,

c) cyano,

d) -NR ^zd R ^ze ; wherein R ^zd and R ^ze are independently selected from hydrogen, C _1-6 alkyl and (C _1-6 alkyl)carbonyl, wherein C _1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, halogen and C _{1 -6} alkoxy,

e) -C(=O)-NR ^zf R ^zg ; wherein R ^zf and R ^zg are independently selected from hydrogen, C _1-6 alkyl and (C _1-6 alkyl)carbonyl, wherein C _1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, halogen and C _{1 -6} alkoxy,

f) -S(=O) _n7 -R ^zh ; where n7 is an integer from 0 to 2, R ^zh represents a hydrogen atom or C _1-6 alkyl,

g) C _1-6 alkyl; wherein C _1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NR ^zr R ^zj , C 1-6 alkoxy and 3-12 membered heterocyclyl, where R ^zi and R ^zj independently represent a hydrogen atom or C1-6alkyl, and where the 3-12 membered heterocyclyl is optional

- 7 044109 is optionally substituted with one or more substituents independently selected from hydroxy, C ₁ . _b alkyl and 312-membered heterocyclyl,

h) C ₁ _ _b alkoxy; where C ₁ _ _b alkoxy is optionally substituted with one or more substituents independently selected from hydroxy, halogen atom and C _1-6 alkoxy,

i) 3-12 membered heterocyclyl; _{wherein the 3-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from C1_6alkyl and (C1_6alkyl ) carbonyl ,}

j) C _6-10 aryl; wherein the C ₆ - ₁₀ aryl is optionally substituted with one or more (C ₁ . _b alkyl)carbonyls, and

k) 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl is optionally substituted with one or more substituents independently selected from C ₁ . ₆ alkyl, C ₁ . ₆ alkoxy, -NR ^zk R ^zl and 3-12 membered heterocyclyl, where R ^zk and R ^zl are independently selected from a hydrogen atom, C ₁ . _b αlkyl and (C ₁ . ₆ alkyl)carbonyl and where the 3-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from alkyl and (C ₁ . ₆ alkyl)carbonyl.

When C ₁ . _b alkyl in ^Rzd , ^Rze , ^Rzf and ^Rzg is replaced by hydroxy, _C1 . _b alkyl, preferably C ₂ - _b alkyl, and more preferably C ₂ .4 alkyl. When C ₁ . _b αlkoxy, substituted with hydroxy, C ₁ . _b alkyl, preferably C ₂ . _b alkyl, and more preferably C _2-4 alkyl.

Preferably, Z ² is selected from i) C3.15 cycloalkyl, which is optionally substituted with one or more -NR ^zd R ^ze , ii) C6-10 aryl, which is optionally substituted with one to three substituents independently selected from group C and iii) 5-10- heteroaryl member which is optionally substituted with one to three substituents independently selected from group D.

More preferably, Z ² is selected from i) C _6-10 aryl, which is optionally substituted with one to three substituents independently selected from the group C and ii) 5-10 membered heteroaryl, which is optionally substituted with one to three substituents independently selected from the group D.

Group C:

a) halogen atom,

b) -NR ^zd2 R ^ze2 ; where R ^zd2 and R ^ze2 are independently selected from the hydrogen atom, C ₁ . _b αlkyl and (C ₁ . _b αlkyl)carbonyl, where C ₁ . _b αlkyl is optionally substituted with one or more C ₁ . _b alkoxy,

c) -S(=O) _n 7-R ^zh1 ; where n7 is an integer from 0 to 2, R ^zh1 represents C ₁ . _b alkyl,

d) C ₁ . _b alkyl,

e) C ₁ . _b alkoxy; where C ₁ . _b alkoxy is optionally substituted with one or more hydroxy,

f) 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl is optionally substituted with one or more substituents independently selected from -NR ^zk1 R ^zl1 , wherein R ^zk1 and R ^zl1 are independently selected from hydrogen and C ₁ . _b alkyl.

Group D:

a) oxo,

b) halogen atom,

c) C ₁ . _b αlkyl; where C ₁ . _b alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C ₁ . _b αlkoxy and 3-12 membered heterocyclyl, wherein the 3-12 membered heterocyclyl is optionally substituted with one or more C ₁ . _b alkyls, and

d) 3-12 membered heterocyclyl.

The compound represented by formula (I) of the present invention is preferably such that Z ¹ represents a group represented by formula (IIIa), Y represents -C(=O)-, R ⁹ represents a group represented by formula (IIb), R ^9b represents a hydrogen atom, R ⁷ and R ⁸ together with the carbon atom to which they are attached form a C ₃ - ₁₅ cycloalkane ring, which is substituted with one to three C ₁ . _b alkyls, and one to three C ₁ . _b alkyls are unsubstituted. Next, examples of the method for producing the compound represented by formula (I), a pharmaceutically acceptable salt or solvate thereof, or a compound or a salt of a compound are explained in the following diagrams.

The compound represented by formula (I), a salt or solvate thereof or a compound or a salt of a compound is prepared by using i) a general production method A1 or a general production method A2, ii) a general production method B and iii) a general production method C. This production method is one example of a preferred method for preparing a compound of formula (I) in which Z ¹ represents a group represented by formula (IIIa), Y represents -C(=O)-, R ⁹ represents a group represented by formula (IIb), and R ^9b represents a hydrogen atom, i.e. the compound represented by formula (Ia).

Also an example of a preferred method of preparing a compound is where R ⁷ and R ⁸ together with the carbon atom to which they are attached form a C ₃ - ₁₅ cycloalkane ring substituted with 1 to 3 C ₁ . _b alkyl groups, where the alkyl groups are not substituted.

It should be noted that in the case where the starting material or the target product of a given step undergoes an undesired chemical transformation under the reaction conditions of a given step, it is possible to obtain the target product of a given step by protecting or deprotecting the functional group. For the selection of the protecting group and the method of protection and deprotection, T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, Inc., New York (2007), can be used. Some examples of methods for protecting and deprotecting a functional group

- 8 044109 groups are shown in the diagram below.

General method for obtaining A1.

Compound f can be prepared by the general production method of A1, illustrated by the following scheme.

Chemical formula 11

where P ² represents a hydrogen atom or C1-6 alkyl, C ^1a represents a protecting group for an amino group, P ^3a and P ^3b independently represent C1-6 alkyl, or P ^3a and P ^3b together with the oxygen atoms to which they are attached, and carbon atom to which oxygen atoms are attached can form a 5-7 membered 1,3-dioxacycloalkane ring, Y ¹ represents cyano or CO-OP ² , Y ² represents =O or =NH, and X ¹ represents the leaving group.

The protecting group for the amino group includes, for example, formyl, (C _1-6 alkyl)carbonyl (acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), carbamoyl, C _1-6 alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl , isopropyloxicarbonil, Tuesday-butoxicarbonil, Tretbotoxicarbonil, etc.), replaced by selil (trimethylilil, triathylilil, trizopropilil, trortbileldimethylille, third-butyldiphenilil, etc.), araloxicarbonil (gasoloxicarbonil, 9fluorenyloxicarbonil, etc.), etc.) Lil , and aralkyl. The leaving group includes, for example, halogen atom, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy, paratoluenesulfonyloxy.

Stage A1-1a.

Compound a1 can be obtained by contacting compound a with a base.

Examples of the base include metal hydrides such as sodium hydride, potassium hydride, lithium hydride; and metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide and lithium t-pentoxide. A metal alkoxide such as potassium tert-butoxide is preferred.

Examples of the solvent include ethereal solvents such as tetrahydrofuran (THF), diethyl ether and dioxane, and THF is preferred. The reaction temperature is usually -30 to 30°C, preferably -10 to 10°C.

The reaction time is usually from 15 minutes to 5 hours, preferably from 30 minutes to 3 hours.

Compound a1 can be isolated, or it can be transferred to step A1-1b without isolation.

Compound A can be obtained as a commercially available product from Aldlab Chemicals, LLC or Tokyo Chemical Industry Co., Ltd. It can also be synthesized according to the method described in Bioorganic Medicinal Chemistry, 1999, 7, 795-809, or CN 103086955.

It should be noted that compound a1 can be obtained as an alkali metal salt such as a potassium salt by contacting with a base used in the reaction, and such a salt can be carried to the next step.

Stage A1-1b.

Connection a1 may be brought into contact with connection a2 to form connection b. This reaction should preferably be carried out in the presence of an acid.

- 9 044109

Examples of the acid include, for example, acids such as hydrochloric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, and salts of a weak base and a strong acid such as pyridinium hydrochloride.

Examples of the solvent include hydrocarbon solvents (hexane, heptane, benzene, toluene, xylene, etc.), and alcohol solvents (methanol, ethanol, etc.). In addition, water may be present in the reaction mixture.

The reaction temperature is usually from 40 to 200°C, preferably from 60 to 150°C.

The reaction time is usually from 6 minutes to 30 hours, preferably from 30 minutes to 3 hours.

Compound a2 can be obtained as a commercially available hydrochloride from Alfa Aesar, etc. Referring to Synlett, 2011, 17, 2555-2558, compound a2, the hydrazine portion of which is protected by a tert-butoxycarbonyl group, can be used after deprotection with an acid such as methanesulfonic acid. Also, referring to Journal of Medicinal Chemistry 2003, 46, 15461553, compound a2 can be prepared using compound: Q1-NH ₂ as a starting compound.

Stage A1-2.

Compound b may be contacted with compound b1 or compound b2 in the presence of a base to produce compound c.

Examples of base include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc.) , metal hydrides such as sodium hydride, potassium hydride, lithium hydride; and metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide and lithium t-pentoxide. When using compound b2, a metal alkoxide such as potassium tert-butoxide is preferred.

Examples of solvents that can be used include alcohol solvents such as methanol and ethanol; ethereal solvents such as THF and diethyl ether; ester solvents such as ethyl acetate and methyl acetate; nitrile-based solvents such as acetonitrile, benzonitrile and benzyl cyanide; amide-based solvents such as N,Ndimethylacetamide (DMA), N-dimethylimidazolidinone (DMI), and DMF. An amide solvent such as DMA is preferred.

The reaction temperature is usually -50 to 70°C, preferably -30 to 50°C.

The reaction time is usually from 15 minutes to 72 hours, preferably from 1 to 30 hours. Compound b1 can be commercially obtained from Enamine LTD. etc. Referring to WO 2006/048727, compound b1 can be produced by contacting the compound: H ₂ NCH ₂ CH(OP ^3a )(OP ^3b ) and phosgene or triphosgene. Compound b2 can be obtained commercially from UkrOrgSyntez Ltd. etc. Referring to WO 99/50262, compound b2 can be prepared by contacting: H ₂ NCH ₂ CH(OP ^3a )(OP ^3b ) and a diisocyanate such as CDI.

Stage A1-3.

Compound c can be contacted with an acid to produce compound d.

Examples of the acid include inorganic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acid (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), and carboxylic acid, ( formic acid (FA), acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid, trifluoroacetic acid (TFA) , tartaric acid, propionic acid, glutaric acid, etc.).

Examples of the solvent include ether solvents (ether, tetrahydrofuran (THF), dioxane, dimethoxyethane, cyclopentyl methyl ether, etc.), aromatic hydrocarbon solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon solvents ( pentane, hexane, heptane, octane, cyclohexane, etc.), amide-based solvents (N,N-dimethylformamide, N,Ndimethylacetamide, N-methylpyrrolidone), alcohol solvents (methanol, ethanol, 2,2,2-trifluoroethanol , n-propanol, isopropanol, n-butanol, sec-butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, etc.) , solvents based on acetic acid esters (methyl acetate, ethyl acetate, isopropyl acetate), acetonitrile and mixtures thereof. An ethereal solvent such as tetrahydrofuran is preferred.

The reaction temperature is usually from 0 to 100°C, preferably from 10 to 80°C.

The reaction time is usually from 10 minutes to 20 hours, preferably from 30 minutes to 5 hours.

Stage A1-4.

a) When Z ² is C ₁ . ₆ alkyl, C ₃ - ₁₅ cycloalkyl and 3-12 membered heterocyclyl, compound d can be contacted with compound d1 in the presence of a base to give compound e.

Examples of the base include metal hydrides such as sodium hydride, potassium hydride and

- 10 044109 lithium; metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide and lithium t-pentoxide; and alkyl metals such as butyllithium and ethyl lithium. Examples of the solvent include ether solvents (ether, tetrahydrofuran (THF), dioxane, dimethoxyethane, cyclopentyl methyl ether, etc.), aromatic hydrocarbon solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon solvents ( pentane, hexane, heptane, octane, cyclohexane, etc.) and amide-based solvents (N,Ndimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.). An amide-based solvent such as N,N-dimethylacetamide is preferred.

The reaction temperature is usually from 0 to 150°C, preferably from 20 to 120°C.

The reaction time is usually from 15 minutes to 24 hours, preferably from 30 minutes to 5 hours.

b) When Z ² is Cb.1oaryl, and 5-10 membered heteroaryl, compound D can be contacted with compound dl in the presence of a base, a copper catalyst and a ligand to give compound e.

Examples of the base include a weak basic inorganic salt (sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate, etc.) and an organic base (triethylamine, pyridine, tetrabutylammonium fluoride, etc.). Preferred is a slightly alkaline inorganic salt such as potassium carbonate.

Examples of the copper-based catalyst include copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(I) acetate, copper(II) oxide and copper(I) trifluoromethanesulfonate, and copper(I) iodide is preferred .

Examples of the ligand include phenanthroline, quinolin-8-ol, 2,2,6,6-tetramethylheptane-3,5-dione, and diamines such as N,N'-dimethylethane-1,2-diamine, trans-cyclohexane-1 ,2-diamine and trans-N,N'dimethylcyclohexane-1,2-diamine and trans-N,N'-dimethylcyclohexane-1,2-diamine are preferred.

Examples of the solvent include ether solvents (ether, tetrahydrofuran (THF), dioxane, dimethoxyethane, cyclopentyl methyl ether, etc.), aromatic hydrocarbon solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon solvents ( pentane, hexane, heptane, octane, cyclohexane, etc.), amide-based solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), alcohol solvents (methanol, ethanol, 2. 2,2trifluoroethanol, n-propanol, isopropanol, n-butanol, sec-butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5pentanediol, etc. ), acetic acid ester solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.), and acetonitrile, and an amide solvent such as N-methylpyrrolidone are preferred.

The reaction temperature is usually from 30 to 200°C, preferably from 60 to 160°C.

The reaction time is usually from 1 to 15 hours, preferably from 3 to 9 hours.

Stage A1-5.

The protecting group of compound e can be removed to obtain compound f. When the protecting group P ^1a is a C1_ ₆ alkoxycarbonyl such as t-butoxycarbonyl, it is preferable to use an acid to remove the protecting group.

Examples of the acid include inorganic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acid (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), and carboxylic acid, ( formic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid, propionic acid , glutaric acid, etc.).

Examples of the solvent include ether solvents (tetrahydrofuran, methyltetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, etc.), hydrocarbon solvents (hexane, heptane, benzene, toluene, etc. ), amide-based solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.) and halogen-containing solvents (dichloromethane, chloroform, carbon tetrachloride, etc.), and an amide-based solvent such as N-methylpyrrolidone is preferred.

The reaction temperature is usually from 0 to 200°C, preferably from 10 to 120°C.

The reaction time is usually from 30 minutes to 10 hours, preferably from 1 to 6 hours.

It should be noted that compound f can be obtained as a salt with the acid used in the reaction, and such a salt can be carried to the next step.

General method for obtaining A2.

When Z ² represents a bulky group such as C ₃ _ ₁₅ cycloalkyl, which is substituted by -NR ^zd R ^ze , it is possible to prepare compound p corresponding to compound f through the general preparation method of A2, as shown in the following scheme.

- 11 044109

Chemical formula 12

R’ R* and’ i*

In the formulas, Z ^2a represents unsubstituted C3-15 cycloalkyl or 3-12 membered heterocyclyl. and P ^1a and P ^2a are protecting groups for an amino group, X ² , X ³ , X ⁴ and X ⁵ independently represent a leaving group, R ^10a and R ^10b independently represent C1-6alkyl, or R ^10a and R ^10b together with atoms oxygen to which they are connected and the carbon atom to which the oxygen atoms are attached can form a 5-7 membered 1,3 dioxacycloalkane ring.

Examples of the amino group protecting group include formyl, (C _1-6 alkyl)carbonyl (acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), carbamoyl, C _1-6 alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl , sec-butoxycarbonyl, tert-butoxycarbonyl, etc.), substituted silyl (trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.), aralkyloxycarbonyl (benzyloxycarbonyl, 9fluorenylmethyloxycarbonyl, etc.), allyl, aralkyl . Examples of the leaving group include halogen atom, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy and paratoluenesulfonyloxy.

Stage A2-1.

Compound g can be contacted with an azide in the presence of a base to produce compound h.

Examples of base include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.).

Examples of the azide include metal azides such as sodium azide, trimethylsilyl azide, and diphenylphosphoryl azide, with diphenylphosphoryl azide being preferred.

Examples of the solvent include ether solvents (tetrahydrofuran, methyltetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, etc.), hydrocarbon solvents (hexane, heptane, benzene, toluene, etc. ), and amide-based solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone) and a hydrocarbon solvent such as toluene are preferred.

The reaction temperature is usually from 0 to 150°C, preferably from 10 to 100°C.

The reaction time is usually from 1 hour to 10 hours, preferably from 2 to 6 hours. Compound g is described, for example, in Journal of the American Chemical Society, 2016, 138, 1698-1708 and WO 2009/152133. It can also be obtained commercially from Enamine Ltd.

Stage A2-2.

Compound b obtained in step A1-1b can be contacted with compound h in the presence of a base to produce compound i.

Examples of base include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), and nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc. .d.). Examples of the solvent include ether solvents such as tetrahydrofuran (THF), diethyl ether, dioxane, and a hydrocarbon solvent such as hexane, heptane, benzene, toluene, etc. A base such as pyridine may also be used as a solvent.

The reaction temperature is usually from 0 to 60°C, preferably from 5 to 45°C.

- 12 044109

The reaction time is usually from 30 minutes to 50 hours, preferably from 2 to 10 hours.

Stage A2-3.

Compound i may be contacted with compound i1 or compound i2 in the presence of a base to produce compound j.

The base includes a weak basic inorganic salt (sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate, etc.) and metal hydrides (sodium hydride, potassium hydride, etc.), and a weak basic inorganic salt such as cesium carbonate is preferred.

Examples of compound i1 include 1,2-dichloro-1-methoxyethane, 1,2-dichloro-1-ethoxyethane, and 1,2-dichloro-1-iso-propoxyethane and 1,2-dichloro-1-tert-butoxyethane, and 1. 2-dichloro-1-ethoxyethane is preferred. Compound i1 can be commercially obtained from Tokyo Chemical Industry Co., Ltd. or FCH Group. Examples of compound i2 include 2-chloro-1,1-dimethoxyethane, 2-chloro-1,1-diethoxyethane, 2-bromo-1,1-dimethoxyethane, and 2-bromo-1,1-ethoxyethane. Compound i2 can be commercially obtained from Tokyo Chemical Industry Co., Ltd.

Examples of the solvent include alcohol solvents such as methanol and ethanol; ethereal solvents such as THF, diethyl ether; ester solvents such as ethyl acetate, methyl acetate; nitrile-based solvents such as acetonitrile, benzonitrile, benzyl cyanide; and amide-based solvents such as N,N-dimethylacetamide (DMA), N N-dimethyl imidazolidinone (DMI), DMF. An amide solvent such as DMA is preferred. The reaction temperature is usually from 0 to 60°C, preferably from 20 to 45°C.

The reaction time is usually from 1 to 72 hours, preferably from 12 minutes to 35 hours.

Stage A2-4.

Compound j may be brought into contact with an acid to produce compound k. Examples of the acid include inorganic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acid (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid acid, etc.), and carboxylic acid, (formic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid, propionic acid, glutaric acid, etc.) and sulfonic acid such as methanesulfonic acid is preferred.

Examples of the solvent include ethereal solvents such as tetrahydrofuran (THF), diethyl ether and dioxane, and THF is preferred.

The reaction temperature is usually from 0 to 100°C, preferably from 20 to 80°C.

The reaction time is usually from 15 minutes to 6 hours, preferably from 30 minutes to 3 hours.

Stage A2-5.

Compound k can be contacted with compound k1 in the presence of a base to produce compound 1.

Examples of compound k1 include C ₁ . ₆ alkyl halides such as methyl iodide, and (C ₁ . ₆ alkyl)carbonyl halides such as acetyl chloride. When R ^ZD is (C ₁ . ₆ alkyl)carbonyl, it is preferable to use an acid anhydride that is present as ((C ₁ . ₆ alkyl)carbonyl) ₂ O, for example acetic anhydride instead of compound k1.

Examples of the base include metal hydrides such as sodium hydride, potassium hydride and lithium hydride; and metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide and lithium t-pentoxide. A metal alkoxide such as potassium pentoxide is preferred.

Examples of the solvent include ether solvents such as tetrahydrofuran (THF), diethyl ether, dioxane, and a hydrocarbon solvent such as hexane, heptane, benzene, toluene. THF is preferred.

The reaction temperature is usually -50 to 50°C, preferably -40 to 40°C.

The reaction time is usually from 1 minute to 2 hours, preferably from 3 to 30 minutes.

Stage A2-6.

The protecting group of Compound 1 can be removed to obtain Compound T. A suitable reagent or reaction conditions can be selected according to the type of protecting group when deprotecting. When the protecting group is tert-butoxycarbonyl, reaction with an acid is preferred. Examples of the acid include inorganic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acid (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), and carboxylic acid, ( formic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid, propionic acid , glutaric acid, etc.) and a carboxylic acid such as trifluoroacetic acid is preferred.

Examples of the solvent include ethereal solvents such as diethyl ether, THF, dimethoxyethane, etc.; halogen-containing solvents such as dichloromethane (CH2Cl2), chloroform, carbon tetrachloride; N,N-dimethylformamide; and acetonitrile. Preferred is a halogenated solvent such as CH ₂ Cl ₂ .

The reaction temperature is usually from 0 to 60°C, preferably from 10 to 40°C.

The reaction time is usually from 30 minutes to 10 hours, preferably from 1 hour to 5 hours. It should be noted that compound m can be obtained as a salt with the acid used in the reaction, and such a salt can be transferred to step A2-7.

Stage A2-7.

The amino group of compound m may be protected to give compound n. A suitable reagent or reaction conditions can be selected according to the type of protecting group when setting the protecting group. When the protecting group is C _1-6 alkoxycarbonyl, reaction with a base is preferred. Examples of compounds used for protection include methoxycarbonyl chloride, ethoxycarbonyl chloride, 2,2,2-trichloroethoxycarbonyl chloride, benzoyl chloride (Z-Cl), 9fluorenylmethyloxycarbonyl (Fmoc-Cl) chloride and di-tert-butyl dicarbonate, and di-tert-butyl dicarbonate is preferred. Examples of base include tertiary amines (triethylamine, Nmethylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), and nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc. .) and a tertiary amine such as triethylamine is preferred. Examples of the solvent include ethereal solvents such as diethyl ether, THF, dimethoxyethane, etc.; halogen-containing solvents such as dichloromethane (CH ₂ Cl ₂ ), chloroform, carbon tetrachloride; N,N-dimethylformamide; and acetonitrile. Preferred is a halogen-containing solvent such as CH ₂ Cl ₂ .

The reaction temperature is usually from 0 to 60°C, preferably from 15 to 40°C.

The reaction time is usually from 30 minutes to 20 hours, preferably from 1 to 5 hours.

Stage A2-8.

Compound n can be brought into contact with compound n1 in the presence of a base to produce compound o.

Examples of compound nl include C _1-6 alkyl halides such as methyl iodide, and (C _1-6 alkyl)carbonyl halide such as acetyl chloride. When R ^ze is C _1-6 alkyl, it is preferred that the C _1-6 alkyl is either unsubstituted or substituted with C _1-6 alkoxy.

This step is carried out similarly to step A2-5, and the base and solvent used in the reaction, and the reaction temperature, reaction time are similar to those in step A2-5.

Stage A2-9.

The protecting group of compound o can be removed to obtain compound p. A suitable reagent or reaction conditions can be selected according to the type of protecting group when deprotecting. When the protecting group P ^1a is a C _1-6 alkoxycarbonyl, such as tert-butoxycarbonyl, deprotection using an acid is preferred. This step is carried out similarly to step A1-5, and the acid and solvent used in the reaction, and the reaction temperature, reaction time are similar to those in step A1-5.

The general method of obtaining V.

Compound bf can be prepared by the general method for preparing B, as shown in the following diagram.

Chemical formula 13

In the formulas, P ²¹ represents hydroxy, C1-6 alkoxy, or -NR ^21a R ^21b , and R ^21a and R ^21b independently represent hydrogen, C 1-6 alkyl or C _6-10 aryl,

X ²¹ represents a hydrogen atom, a halogen atom, or -Zn-X ^21a , X ^21a represents a bromine atom or an iodine atom, and

X ²² represents the leaving group.

- 14 044109

The leaving group includes, for example, halogen atom, acetyloxy, trifluoroacetyloxy, methanesulfonyloxy, paratoluenesulfonyloxy.

Stage B-1.

Compound ba can be contacted with compound ba1 in the presence of a paldium catalyst to produce compound bb.

The complex formed in the reaction mixture by separately adding the palladium compound and the ligand can be used as a palladium catalyst. The complex obtained separately can be used. Examples of the ligand include 4,5-bis(diphenylphosphino)-9,9dimethylxanthene, trimethylenebis(diphenylphosphine), 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-(di- tert-butylphosphino)-2',4',6'-triisopropyl3,6-dimethoxy-1,1'-biphenyl and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl. Examples of palladium compounds that can be combined with the ligand include, for example, di-μ-chlorobis[(ηallyl)palladium(II)], tetrakis(triphenylphosphine)palladium(0).

Examples of palladium catalyst that can be used in the present step include tris(dibenzylideneacetone)dipalladium(0), 5,10,15,20-tetraphenyl-21H,23H-porphine cobalt(II), palladium(II) acetate, bis( di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), [1,1'bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichlorodichloromethane adduct, dichlorobis(triphenylphosphine)palladium(II) palladium hydroxide, tetrakis(triphenylphosphine )palladium(0) and di-μchlorobis[(p-allyl)palladium(II)]. It is preferable to use a complex formed from the palladium compound, di-μ-chlorobis [(p-allyl)palladium(II)], and the ligand, 2-(di-tert-butylphosphino)-2',4',6'triisopropyl-1 ,1'-biphenyl as catalyst in step 11. It should be noted that the step can be carried out in the presence of a base. Examples of the base include weak basic inorganic salt (sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, calcium acetate, etc.), metal hydrides (sodium hydride, potassium hydride, etc.), and metal alkoxides (potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-pentoxide, sodium tert-pentoxide, lithium tert-pentoxide, etc.).

Examples of the reaction solvent include ethereal solvents such as tetrahydrofuran (THF), diethyl ether, dioxane, etc.; amide-based solvents such as N,Ndimethylacetamide (DMA), N N-dimethyl imidazolidinone (DMI), DMF. The solvent may be a mixture of solvent and water.

The reaction temperature is usually from 10 to 200°C, preferably from 40 to 130°C.

The reaction time is usually from 1 minute. up to 20 hours, preferably from 10 minutes to 10 hours.

Compound ba can be obtained commercially from Aurora Fine Chemicals. It can also be prepared by the procedure described in Synthetic Communications, 39 (14), 2506-2515, 2009. It can also be prepared by esterification or amidation of compound ba, where -COP ²¹ is -COOH.

Compound ba1, where X ²¹ is -Zn-X ^21a , can be obtained commercially from Focus Synthesis LLC. Or it can be obtained according to the method described in WO 2014/201206.

Stage B-2.

Compound bb may be contacted with compound bb1 in the presence of a base to produce compound bc.

Examples of the base include metal hydrides such as sodium hydride, potassium hydride, etc., and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide, and potassium hydroxide is preferred.

Examples of the reaction solvent include amide-based solvents such as N,Ndimethylacetamide (DMA), N-dimethylimidazolidinone (DMI), and DMF, and DMI is preferred. The solvent may be a mixture of solvent and water.

The reaction temperature is usually from -10 to 100°C, preferably from 0 to 45°C.

The reaction time is usually from 30 minutes to 10 hours, preferably from 1 to 5 hours. Compound bb can be obtained commercially from Aquila PharmaTech LLC. It can be obtained according to the method described in WO 2013/010904, Organic Letters, 7 (18), 3965-3968, 2005 or US 5998438.

Stage B-3.

Compound bc can be contacted with hydroxylamine (H2NOH) to produce compound bd.

Examples of the reaction solvent include aprotic polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetamide and 1-methyl-2-pyrrolidone, and alcohol solvents such as methanol and ethanol, and DMSO is preferred. The solvent may be a mixture of solvent and water. The reaction temperature is usually from -10 to 100°C, preferably from 20 to 45°C.

The reaction time is usually from 2 to 72 hours, preferably from 3 to 36 hours. Compound bd can be transferred to step B-4 without isolation or purification.

- 15 044109

Stage B-4.

Compound bd may be contacted with triphosgene, a chlorocarboxylic acid ester (methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate, etc.), carbonyldiimidazole, etc., preferably carbonyldiimidazole in the presence of a base, to obtain compound be. Examples of base include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, 1,8-diazabicycloundec-7-ene (DBU), DABCO, etc.), and metal hydroxides (sodium hydroxide, potassium hydroxide) and tertiary amine, such as DBU is preferred.

Examples of the solvent include aprotic polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetamide and 1-methyl-2-pyrrolidone, alcohol solvents such as methanol and ethanol, and ether solvents such as tetrahydrofuran (THF), diethyl ether, and dioxane, and DMSO is preferred.

The reaction temperature is usually from -10 to 100°C, preferably from 20 to 45°C.

The reaction time is usually from 10 minutes to 10 hours, preferably from 15 minutes to 2 hours.

Stage B-5.

The protecting group of compound be, with the protecting group P ²¹ , can be removed using a base to obtain compound bf.

Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide; and metal alkoxides such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide and lithium t-pentoxide.

Examples of the solvent include alcohol solvents such as methanol, ethanol, methoxyethanol, tert-butyl alcohol; ethereal solvents such as THF, diethyl ether; and amide-based solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylimidazolidinone (DMI), and DMF. The solvent may also be a mixture of solvent and water.

The reaction temperature is usually from -20 to 120°C, preferably from 20 to 100°C.

The reaction time is usually from 20 minutes to 10 hours, preferably from 30 minutes to 5 hours.

Please note that the order of stages B-1, B-2, B-3, B-4 and B-5 may be changed. For example, compound ba may be subjected to steps B-2 and B-1 sequentially to produce compound bc. Compound ba can be sequentially subjected to steps B-2, B-3, B-4, B-5 and B-1 to obtain compound bf. Compound ba can be sequentially subjected to steps B-2, B-3, B-4, B1 and B-5 to obtain compound bf.

Stage B-Aa and stage B-Ab.

In addition, when X ²¹ represents a halogen atom, compound ba can be transferred to the next step B-Aa and B-Ab to obtain compound bb, and compound bb can also be transferred to step B-2.

Chemical formula 14

In the formulas, RQ ^c and RQ ^d independently represent a hydrogen atom or a C _1-6 alkyl, or RQ ^c and RQ ^d together with the oxygen atoms to which they are attached, and the carbon atom to which the oxygen atoms are attached may form 1,3 ,2-dioxaborolanyl or 1,3,2-dioxaborinanyl.

Stage B-Aa.

Compound ba can be contacted with compound ba2 or compound Ba3 in the presence of a palladium catalyst to produce organoboron compound baa. This step can be carried out in the presence of a base. This step is carried out similarly to Step B-1, and the palladium catalyst, base, solvent used in the reaction, or the reaction temperature and reaction time are the same as those in Step B-1.

Examples of compound ba2 include pinacolborane, 4,6,6-trimethyl-1,3,2-dioxaborinan. Compound ba3 includes, for example, diboronic acid, pinacoldiborane (4,4,4',4',5,5,5',5'-octamethyl-2,2'bis(1,3,2-dioxaborolane)), bis (neopentylglycolato)diborone and bis(hexyleneglycolato)diborone. These compounds can be obtained as a commercial product from Tokyo Chemical Industry Co., Ltd. Or by the procedure described in the Journal of American Chemical Society, 131 (45), 16346-16347, 2009 or Organic Synthesis, 77, 176-185, 2000, they can also be prepared using i) pinacol and ii) diborane, complex VN ₃ · THF or complex VN ₃ · dimethyl sulfide.

Organoboron compound baa can be transferred to the B-Ab stage without isolation.

- 16 044109

Stage B-Ab.

Organoboron compound baa can be contacted with compound ba1 in the presence of a base to produce compound bb.

Examples of the base include a weak basic inorganic salt (sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), and sodium carbonate is preferred.

The solvent used in the reaction or the reaction temperature and reaction time are the same as those in step B-1.

It should be noted that the conversion of compound ba1 to an organoboron compound, similar to the conversion of compound ba to compound baa, and then bringing it into contact with compound ba also leads to compound bb.

Stage B-B.

In addition, when the compound bb1 is represented by X ²¹ -(CH ₂ ) _nl -CH ₂ -CN, the compound bca corresponding to the compound bc obtained in step B-2 can be transferred to the BB step, i.e. is brought into contact with compound bc1 in the presence of a base to produce compound bcb corresponding to compound bc in which R ⁷ and R ⁸ together with the carbon atom to which they are attached form

The C _3-15 cycloalkane ring and the C _3-15 cycloalkane ring formed by the union of R ⁷ and R ⁸ can be substituted with one to three C _1-6 alkyls, and the resulting compound can be transferred to step B.

Chemical formula 15

In the formulas R ^7c , R ^7e and R ^7d , present in n8, each independently represents a hydrogen atom or Ci-6 alkyl, and n8 is an integer from 0 to 3. The base includes, for example, metal hydrides such as sodium hydride , potassium hydride, lithium bis(trimethylsilyl)amide (LiHMDS) and sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA) and lithium 2,2,6,6-tetramethylpyrrolidide and KHMDS are preferred.

The solvent includes, for example, ether solvents such as THF, diethyl ether and dioxane, amide solvents such as N,N-dimethylacetamide (DMA), N,Ndimethylimidazolidinone (DMI), DMF, N,N dimethylpropylene urea (DMPU), and an amide-based solvent such as DMPU is preferred.

The reaction temperature is, for example, from -20 to 40°C, preferably from -10 to 10°C.

The reaction time is, for example, from 30 minutes to 8 hours, preferably from 1 to 4 hours.

Compound bc1 can be obtained as a commercial product from CGeneTech. Inc. It can also be obtained by the method described in Organic Letters, 12 (17), 3938-3941, 2010.

General method for obtaining C.

Stage C-1.

Chemical formula 16

Compound f (or compound p) and compound bf can be put into a condensation reaction using a condensing agent in the presence of a base, and compound (Ia) can be obtained.

Examples of the condensing agent include BOP-based condensing agents such as benzotriazol-1-yloxy-tris(dimethylamino)phosphonium (BOP), benzotriazol-1-yloxy-tris(pyrrolizino)phosphonium (PyBOP (registered trademark)), PyAOP , BroP, PyCloP, PyBroP (registered trademark), DEPBT; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride H-hydrate (DMT-MM), 2-(1H-benzotriazol-1-yl)-1,1 ,3,3-tetramethyluronium tetrafluoroborate (TBTU), [di- 17 044109 methylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]dimethylazonium hexafluorophosphate (HATU), and ethyl (hydroxyimino)cyanoacetate (Oxyma). HATU is preferred.

Examples of base include tertiary amines (triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, DABCO, etc.), and nitrogen-containing aromatic compounds (pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine, pyrazine, pyridazine, etc. .d.) and a tertiary amine such as diisopropylethylamine is preferred.

Examples of the solvent include ethereal solvents such as tetrahydrofuran (THF), diethyl ether and dioxane, aprotic polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetamide and 1-methyl-2-pyrrolidone, and an aprotic polar solvent such as DMF is preferred.

The reaction temperature is, for example, from 0 to 80°C, preferably from 20 to 60°C.

The reaction time is, for example, from 1 minute to 10 hours, preferably from 30 minutes to 5 hours.

It should be noted that compound (Ia) can be obtained by changing the order of stages, for example, by sequentially introducing compound D in stages A1-5, C-1, A1-4, sequentially introducing compound 6a in stages B-2, B-3 , B-4, B-5, C-1 and B-1.

In addition, the compound represented by formula (I) can be brought into contact with an acid or a base, which can be used in the manufacture of pharmaceutical compositions to obtain a salt thereof. The salt may be any pharmaceutically acceptable salt, and examples of such salts include inorganic acid salts (hydrochloric acid salt, hydrobromic acid salt, hydroiodic acid salt, sulfuric acid salt, phosphoric acid salt, etc.), sulfonic acid salts (methanesulfonic acid salt , ethanesulfonic acid salt, benzenesulfonic acid salt, toluenesulfonic acid salt, etc.), carboxylic acid salts (formic acid salt, acetic acid salt, oxalic acid salt, maleic acid salt, fumaric acid salt, citric acid salt, malic acid salt , succinic acid salt, malonic acid salt, gluconic acid salt, mandelic acid salt, benzoic acid salt, salicylic acid salt, fluoroacetic acid salt, trifluoroacetic acid salt, tartaric acid salt, propionic acid salt, glutaric acid salt, adipic acid salt, salt nicotinic acid, etc.), alkali metal salts (lithium salt, sodium salt, potassium salt, cesium salt, rubidium salt, etc.), alkaline earth metal salts (magnesium salt, calcium salt, etc.), ammonium salts (ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, tetraalkylammonium salt, etc.) and basic amino acid salts (lysine salt, arginine salt, etc.), and alkali metal salts and alkaline earth metal salts are preferred , and sodium salts and calcium salts are even more preferred. For example, the free form of the compound represented by formula (I) can be suspended or dissolved in an alcohol such as methanol and ethanol, or acetonitrile, acetone, dimethyl sulfoxide, etc., and a basic aqueous solution containing sodium ion from sodium hydroxide, etc., a methanol solution containing sodium methoxide or an ethanol solution containing sodium ethoxide is added to obtain the sodium salt of the compound represented by formula (I). The reaction temperature is, for example, from 0 to 80°C, preferably from 20 to 60°C.

The compound represented by formula (1) or a salt thereof may be a solvate or a non-solvate. The solvent contained in the solvate may be water or an organic solvent. Alcohols (eg methanol, ethanol, n-propanol), dimethylformamide, acetonitrile, acetone, dimethyl sulfoxide can be used as an organic solvent. The compound represented by formula (I) and a salt thereof may preferably be used in the form of a hydrate, and it is also preferably used in the form of a non-solvate. The proportion of solvent (preferably water molecule) relative to the compound containing only the compound represented by formula (I) or a salt thereof is, for example, 0.1 to 10, and 0.5 to 6 is more preferable. In addition, the proportion of solvent may fluctuate depending on humidity, production method and season of production.

A solvate of the compound represented by formula (I) or a salt thereof can be prepared by a conventional method such as precipitation of the compound represented by formula (1) or a salt thereof from a solvent. In addition, the hydrate can be obtained by precipitation of the compound represented by formula (I) or a salt thereof from an aqueous organic solvent.

The solvate of the compound represented by formula (I) or a salt thereof can be converted into the compound represented by formula (I) or a salt thereof by a conventional method such as heating under reduced pressure.

The compound used as a pharmaceutical agent is preferably the compound represented by formula (I) per se (in free form), free form hydrate, free form salt, and the salt hydrate is more preferably free form, free form hydrate, free form sodium salt, sodium salt hydrate, free form calcium salt and calcium salt hydrate.

The compound represented by formula (I) or a salt or solvate thereof, or a compound or a salt of a compound, according to the present invention can be used in the form of a crystalline or amorphous

- 18 044109 forms.

The present invention includes all stereoisomers of the compound represented by formula (I) (eg, enantiomers, diastereomers (including cis- and trans-isomer geometric isomers)), racemic form of isomers and other mixtures. For example, a compound of this invention may have one or more asymmetric centers, and the invention includes racemic mixture, mixture of diastereomers and enantiomers of such a compound.

This invention includes an embodiment in which the atom included in the compound of the present invention represented by formula (I) is an isotope, and includes an embodiment in which at least one atom is replaced by an atom having the same atomic number (number of protons) and another mass number (sum of protons and neutrons). Examples of isotopes included in the compound of the present invention include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom, chlorine atom, which respectively include ^2H , ^3H , ^13C , ^14C , ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ R, ³² R, ³⁵ S, ¹⁸ F, ³⁶ Cl. In particular, radioisotopes that emit radiation when decaying, such as ^3H or ^14C , are useful in pharmaceutical formulations or in vivo topographic studies of compounds. A stable isotope does not decay, its quantity does not change, and it is not radioactive, so it can be used safely. When the atom that is included in the compound of this invention is an isotope, it can be transformed in accordance with a conventional method by replacing the reagent used in the synthesis with a reagent containing the corresponding isotope. The compound of the present invention, a salt thereof or a solvate thereof have a GLP1 receptor agonist effect and a blood glucose lowering effect, and can be used for the prevention or treatment of non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus diabetes (type 1 diabetes mellitus), diabetic complications, obesity, hypertension, hyperlipidemia, arteriosclerosis, myocardial infarction, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease or dementia when the said compound is administered to patients in the form of a pharmaceutical composition in a pharmacologically effective amount and a suitable route of administration.

The term diabetes, as used herein, describes a condition or disease in which the metabolism, production and use of glucose becomes inadequate due to the body's inability to maintain adequate blood glucose levels and covers insulin-dependent diabetes mellitus (type 1 diabetes) and non-insulin-dependent diabetes mellitus (type 2 diabetes).

The term hyperglycemia, as used herein, refers to a condition in which the fasting or post-glucose infusion plasma glucose level is higher than normal (eg, 80 to 110 mg/dL in a fasting individual), which is a typical symptom of diabetes.

The term impaired glucose tolerance as used herein includes insulin-resistant impaired glucose tolerance and insulin hyposecretion.

The term diabetic complication, as used herein, describes a complication caused by diabetes or hyperglycemia, and it can be acute or chronic complex. The term acute complex as used herein includes ketoacidosis and infectious diseases (eg, skin infection, soft tissue infection, biliary tract infection, respiratory system infection, urinary tract infection), and the term chronic complex as used herein , includes, for example, microangiopathy (eg, nephropathy, retinopathy), neuropathy (eg, sensory nerve disorder, motor nerve disorder, autonomic nerve disorder), and gangrene. The major diabetic complexes include diabetic retinopathy, diabetic nephropathy and diabetic neuropathy. The term coronary heart disease, as used herein, includes myocardial infarction and angina.

The term dementia as used herein includes, for example, Alzheimer's disease, vascular dementia and diabetic dementia. The route of administration may be systemic administration, including oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intravaginal administration, intraperitoneal administration, intravesical administration and inhalation, as well as topical administration by ointment, gels and cream.

When using a compound of this invention, a salt or solvate thereof, or a compound or a salt of a compound in the form of a pharmaceutical composition, it is usually formulated in a specific pharmaceutical composition (dosage form). Examples of such pharmaceutical formulations include tablet, capsule, granules, powders, fine granules, pills, aqueous or non-aqueous solution or suspension. In addition, the compound of the present invention, a salt or solvate thereof, or a compound or a salt of a compound, can also be used in the form of various controlled release formulations. Examples of such controlled release formulations include, for example, those to be incorporated into the body, such as those applied to the oral mucosa or nasal mucosa. The solution or suspension may be placed in storage containers suitable for dividing into appropriate administration amounts. Difference

- 19 044109 These pharmaceutical compositions can be prepared in a well known manner by mixing a compound of the present invention, a salt or solvate thereof, or a salt of a compound and a pharmaceutically acceptable additive. Examples of such additives include, for example, an adjuvant, a lubricant (coating agent), a binder, a disintegrant, a stabilizer, a corrective agent, a base, a dispersant, a diluent, a surfactant, or an emulsifier.

Examples of the excipient include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and dicalcium phosphate.

Examples of the lubricant (coating agent) include ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, talc, carnauba wax and paraffin.

Examples of the binder include polyvinylpyrrolidone, macrogol and compounds that are the same as the above excipient. Examples of the disintegrant include chemically modified starch and cellulose such as croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, and compounds that are the same as the above auxiliary substance.

Examples of the stabilizer include para-hydroxybenzoates such as methylparaben and propylparaben; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

Examples of flavoring agents include sweetener, acidifier and flavoring agent, which are commonly used.

Examples of the base include fats such as lard; vegetable oil such as olive oil and sesame oil; higher alcohols such as stearyl alcohol and cetanol; animal oil; lanolinic acid; petrolatum; paraffin; bentonite; glycerol; and glycol oil.

Examples of dispersants include cellulose derivatives (Arabic rubber, tragacanth, methylcellulose, etc.), polyesters, stearic acid, sorbitan sesquialeate, aluminum monostearate, sodium alginate, polysorbate, and sorbitan fatty acid ester.

Examples of the solvent or diluent in the liquid composition include phenol, chlorocresol, purified water, distilled water, etc.

Examples of the surfactant or emulsifier include polysorbate 80, polyoxyl stearate 40, lauromacrogol.

The content of a compound of this invention, a salt or solvate thereof, or a compound or a salt of a compound in a pharmaceutical composition differs from that in a dosage form, but the difference is generally 0.01 to 100% by weight.

The pharmaceutical composition may contain one type or two or more types of a compound of this invention, a salt thereof, or a solvate thereof of either a compound or salts of a compound.

When using the compound of this invention, a salt or solvate thereof, or a compound or a salt of a compound as a prophylactic agent or therapeutic agent for non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity, the amount to be administered can be suitably determined according to the severity symptom, age, body weight, relative health status, combination with other medications and route of administration. For example, when the subject of administration is a homeotherm, especially a human, the dosage per day is from 0.01 to 10,000 mg, preferably from 0.1 to 1000 mg when administered orally, and from 0.001 to 3000 mg, preferably from 0.01 to 300 mg when administered orally. non-oral administration. It should be noted that the above dosage can be administered from once a day to once every few weeks, or it can be divided into two or more times a day.

An effective amount of a compound of this invention, a salt or solvate thereof, or a compound or a salt of a compound means a therapeutically effective amount or a prophylactically effective amount, and may be appropriately determined according to symptom severity, age, body weight, relative health status, combination with other medications and route of administration.

Examples

The contents of the present invention are explained in more detail using the following examples and reference examples. All starting materials and reagents were obtained from commercial suppliers or prepared according to generally known methods. Room temperature (RT) is a temperature between 5 and 35°C. The silica gel used in this document was obtained from SHOKO Scientific PurifPack (registered trademark) SI 60 µm (Shoko Scientific Co., Ltd.), Biotage (registered trademark) SNAP Ultra Silica Cartridge (Biotage) or SNAP KP-Sil Cartridge ( Biotage reverse phase silica gel was Wakosil (registered trademark) 25C18 (Wako Pure Chemical Industries, Ltd.) or Biotage (registered trademark) SNAP Ultra C18 Cartridge (Biotage). HPLC purification of compounds was performed using an AutoPurification HPLC/MS system (Waters) or a preparative injection/fractionation HPLC system (Gilson). 1H-NMR spectra were recorded with or without Me ₄ Si as internal eta.

- 20 044109 pubic material, and using ECP-400 (JEOL), Agilent 400-MR (Agilent Technologies Japan, Ltd), AVANCE3 300 MHz (Bruker) or AVANCE3 600 MHz Cryo-TCI (Bruker) (s=singlet, bgz= wide singlet, d=doublet, 1=triplet, q=quartet, dd=doublet of doublets, ddd=doublet of doublets of doublets, m=multiplet). To determine the chemical shift in the NMR spectra, Me ₄ Si or a deuterated solvent was used as a standard, and the chemical shifts are presented in ppm. (ppm, δ), and splitting constants (J) are presented in Hz (Hertz). LC/MS was performed by retention time measurement and mass spectrometry was performed using the instrument and analysis conditions specified in Table 1. The microwave reactor used an Initiator™ radiation source (Biotage). LC/MS Macc spectrometry analysis was performed using the following mass spectrometers: SQD (Waters), SQD2 (Waters), 2020 (Shimadzu), or 2010EV (Shimadzu).

Table 1

Instrument and analytical conditions used for LC/MS

LC/MS Analysis Conditions, no. Tool nt Column Mobile phase, gradient and flow rate SMD-FA05-1 nexera/20 20 Speed Core Cl8 2.1mm I.D.x50mm, 2.7 MKM 0.1%FA H ₂ O/0.1%FA MeCN = 95/5 0/100 (1.5 min.) 0/100 (0.5 min.), 1 ml/min. SMD-FA05-2 nexera/20 20 Metoric Core C18 2.1mm I.D.x50mm, 2.7 MKM 0.1%FA H2O/0.1%FA MeCN = 95/5 0/100 (1.5 min.) 0/100 (0.5 min.), 1 ml/min. SMD-FAO5-3 nexera/20 20 Ascentis Express C18 2.1 mm I.D.x50 mm, 2.7 MKM 0.l%FA H2O/0.1%FA MeCN = 95/5 0/100 (1.5 min.) 0/100 (0.7 min.), 1 ml/min. SMD-FA05long nexera/20 20 Speed Core Cl8 2.1mm I.D.x50mm, 2.7 MKM 0.1%FA H2O/0.1%FA MeCN = 05/95 -+ 0/100 (4.5 min.) 0/100 (0.5 min.), 1 ml/min. SMD-FA10-1 UFLCXR/ 2020 Phenomenex Kinetex C18 3.0mm I.D.x50mm, 2.6MKM 0.1%FA H2O/0.1%FA MeCN = 90/10 -+ 0/100 (1.2 min.) 0/100 (0.5 min.), 1.5 ml/min. SMD-FA10-2 UFLCXR/ 2020 Kinetex XB-C18 3.0 mm I.D.x50 mm, 2.6 MKM 0.1%FA H2O/0.1%FA MeCN = 90/10 -+ 0/100 (1.2 min.) 0/100 (0.5 min.), 1.5 ml/min. SMD-FA10-3 UFLCXR/ 2020 Kinetex XB-C18 3.0 mm I.D.x50 mm, 2.6 MKM 0.1%FA H2O/0.1%FA MeCN = 90/10 -+ 0/100 (1.1 min.) 0/100 (0.7 min.), 1.5 ml/min. SMD-FA10-4 UFLCXR/ 2020 Acquity BEH Cl8 2.1 mmI.D.x50 mm, 1.7 MKM 0.1%FA H2O/0.1%FA MeCN = 90/10 -+ 0/100 (1.1 min.) 0/100 (0.5 min.), 0.7 ml/min. SMD-FA10-5 Nexera/20 20 Accucore 2.1mm I.D.x50mm, 2.7MKM 0.1%FA H2O/0.1%FA MeCN = 90/10 -+ 0/100 (1.1 min.) -+ 0/100 (0.5 min.), 1.0 ml/min. SMDFA1060-1 UFLCXR/ 2020 Kinetex XB-C18 3.0 mm I.D.x50 mm, 2.6 MKM 0.1%FA H2O/0.1%FA MeCN = 90/10 -+ 40/60 (4.0 min.) -+ 5/95 (0.5 min.), 1.5 ml/min. SMD-FA10long UFLCXR/ 2020 Phenomenex Kinetex C18 3.0mm I.D.x50mm, 2.6MKM 0.1%FA H2O/0.1%FA MeCN = 90/10 -+ 0/100 (4.5 min.) -+ 0/100 (1.3 min.), 1.1 ml/min. SMD-TFA051 nexera/20 20 Ascentis Express C18 2.1 mm I.D.x50 mm, 2.7 MKM 0.05% TFA H ₂ 0/0.05% TFA MeCN = 95/5 0/100 (1.5 min.) 0/100 (0.5 min.), 1 ml/min. SMD-TFA052 nexera/20 20 Metoric Core C18 2.1mm I.D.x50mm, 2.7MKM 0.05% TFA H ₂ 0/0.05% TFA MeCN = 95/5 -+ 0/100 (1.5 min.) 0/100 (0.5 min.), 1 ml/min. SMD-TFA053 nexera/20 20 Kinetex l,7u C18 2.1 mmI.D.x50 mm, 1.7 MKM 0.05% TFA H ₂ 0/0.05% TFA MeCN = 95/5 0/100 (1.5 min.) 0/100 (0.5 min.), 1 ml/min. SMD-TFA054 nexera/20 20 Ascentis Express C18 2.1mm I.D.x50mm, 2.7 MKM 0.05% TFA H ₂ 0/0.05% TFA MeCN = 95/5 0/100 (1.1 min.) 0/100 (0.5 min.), 1 ml/min. SMD-TFA055 UFLCXR/ 2020 Shim-pack XR-ODS 3.0mm I.D.x50mm, 2.2 MKM 0.05% TFA H ₂ 0/0.05% TFA MeCN = 95/5 -+ 0/100 (1.2 min.) 0/100 (1.0 min.), 1 ml/min. SMD-TFA056 UFLCXR/ 2020 Shim-pack XR-ODS 3.0mm I.D.x50mm, 2.2 MKM 0.05% TFA H ₂ 0/0.05% TFA MeCN = 95/5 -+ 0/100 (2.2 min.) -+ 0/100 (1.0 min.), 1 ml/min. SMD-FA05- R.P. nexera/20 20 Ascentis Express RPAmide 2.1mm I.D.x50mm, 2.7 MKM 0.1%FA H2O/0.1%FA MeCN = 95/5 0/100 (1.5 min.) 0/100 (0.5 min.), 1 ml/min.

- 21 044109

SMD-FA50- R.P. nexera/20 20 Ascentis Express RPAmide 2.1mm I.D.x50mm, 2.7 MKM 0.1%FA H ₂ O/0.1%FA MeCN = 50/50 0/100 (1.0 min.) 0/100 (1.0 min.), 1 ml/min. SMD-TFA05- R.P. nexera/20 20 Ascentis Express RPAmide 2.1mm I.D.x50mm, 2.7 MKM 0.05% TFA H ₂ 0/0.05% TFA MeCN = 95/5 0/100 (1.5 min.) 0/100 (0.5 min.), 1 ml/min. SMD-TFA50- R.P. nexera/20 20 Ascentis Express RPAmide 2.1mm I.D.x50mm, 2.7 MKM 0.05% TFA H ₂ 0/0.05% TFA MeCN = 50/50 0/100 (1 min.) 0/100 (1 min.), 1 ml/min. SQD-FA05-1 Aquity UPLC-IClass/SQ D Ascentis Express C18 2.1mm I.D.x50mm, 2.7 MKM 0.1%FA H ₂ O/0.1%FA MeCN = 95/5 0/100 (1.0 min.) 0/100 (0.4 min.), 0.9 ml/min. SQD-FA05-2 Aquity UPLC-IClass/SQ D Ascentis Express RPAmide 2.1mm I.D.x50mm, 2.7 MKM 0.1%FA H ₂ O/0.1%FA MeCN = 95/5 0/100 (1.0 min.) 0/100 (0.4 min.), 1 ml/min. SQD-FA05-3 Aquity UPLC/SQ D Ascentis Express C18 2.1 mm I.D.x50 mm, 2.7 MKM 0.1%FA H ₂ O/0.1%FA MeCN = 95/5 0/100 (1.0 min.) 0/100 (0.4 min.), 1 ml/min. SQD-FA05-4 Aquity UPLC/SQ D2 Ascentis Express C18 2.1 mm I.D.x50 mm, 2.7 MKM 0.1%FA H ₂ O/0.1%FA MeCN = 95/5 0/100 (1.0 min.) 0/100 (0.4 min.), 1 ml/min. SQD-FA50-1 Equity UPLC-I- Class/SQ D Ascentis Express RPAmide 2.1mm I.D.x50mm, 2.7 MKM 0.1%FA H ₂ O/0.1%FA MeCN = 50/50 0/100 (0.7 min.) 0/100 (0.7 min.), 1 ml/min. SQD-AA05-1 Equity UPLC-I- Class/SQ D Ascentis Express C18 2.1mm I.D.x50mm, 5 MKM YumM AcONH ₄ H ₂ O/MeOH = 95/5 0/100 (1 min.) 100 (0.4 min.), 1 ml/min. SQD-AA05-2 Aquity UPLC/SQ D Ascentis Express C18 2.1 mm I.D.x50 mm, 2.7 MKM YumM AcONH ₄ H ₂ O/MeOH = 95/5 0/100 (1 min.) 100 (0.4 min.), 1 ml/min. SQD-AA50-1 Aquity UPLC/SQ D Ascentis Express C18 2.1mm I.D.x50mm, 2.7 MKM YumM AcONH ₄ H ₂ O/MeOH = 50/50 0/100 (0.7 min.) 100 (0.7 min.), 1 ml/min. SQD-FA05long Equity UPLC-I- Class/SQ D Ascentis Express C18 2.1 mm I.D.x50 mm, 2.7 MKM 0.1%FA H ₂ O/0.1%FA MeCN = 95/5 0/100 (4.5 min.) 0/100 (0.5 min.), 1 ml/min. SQD-FA0550long Equity UPLC-I- Class/SQ D Ascentis Express C18 2.1 mm I.D.x50 mm, 2.7 MKM 0.1%FA H ₂ O/0.1%FA MeCN = 95/5 5/50 (4.5 min.) 0/100 (0.01 min.) —► 0/100 (0.49 min. ), 1 ml/min. SQD-AA50long Aquity UPLC-IClass/SQ D Ascentis Express C18 2.1mm I.D.x50mm, 5 MKM YumM AcONH ₄ H ₂ O /MeOH = 50/50 0/100 (4.5 min.) 100 (0.5 min.), 1 ml/min. SQDAA0550-long Equity UPLC-I- Class/SQ D Ascentis Express C18 2.1mm I.D.x50mm, 5 MKM YumM AcONH ₄ H ₂ O /MeOH = 95/5 50/50 (4.5 min.) 0/100 (0.01 min.) —► 0/100 (0.49 min.), 1 ml/min.

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Example 1. Synthesis of 3-[(1S,2S)-1-[2-[2-(3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2oxoimidazol-1 -yl] -6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(2-ethyl-3-methylpyridin-4yl)indol-1 -yl]-2-methylcyclopropyl] -4H -1,2,4-oxadiazol-5-one (compound 1).

Chemical formula 17

Stage 1-1.

Potassium [(5-cyano-1,2,3,6-tetrahydropyridin-4-yl)amide] (compound 1b) To a solution of 3-(2cyanoethylamino)propanenitrile (compound 1a, 22.0 g, 179 mmol) in tetrahydrofuran ( THF) (179 ml), a solution of 1 M potassium tert-butoxide in THF (179 ml) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, washed with THF (50 ml), and then the filtrate was dried under reduced pressure to give title compound 1b (23.8 g, 83% yield) as a light brown solid.

LC/MS mass spectrometry: m/z 124 ([M+H]+).

LC/MS retention time: 0.14 min (analytical conditions: SMD-FA05-1).

1H-NMR (400 MHz, MeOH-d ₄ ) δ: 3.33 (2H, t, J=1.3 Hz), 2.90 (2H, t, J=5.9 Hz), 2.21 ( 2H, tt, J=5.9, 1.3 Hz).

Stage 1-2.

tert-Butyl-3-amino-2-(3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 1d).

To an ethanol (57.9 ml) solution of 3,5-dimethylphenylhydrazine hydrochloride (compound 1c, 5.00 g, 29.0 mmol) and compound 1b obtained in step 1-1 (4.67 g, 29.0 mmol) , added 2 N. hydrochloric acid (23.2 ml, 46.3 mmol), and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was cooled to 0°C, aqueous 5M sodium hydroxide solution (9.27 ml, 46. 3 mmol) and di-tert-butyl dicarbonate (6.64 g, 30.4 mmol) were added and the mixture was stirred at 0 °C for 1 h. Water was added to the reaction mixture and extracted with ethyl acetate, then the organic layer was washed with saturated aqueous chloride solution sodium and dried with anhydrous magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0:1 to 1:1) to obtain the title compound 1d (7.82 g, 79% yield) as pale yellow solid matter.

LC/MS mass spectrometry: m/z 343 ([M+H]+).

LC/MS retention time: 0.99 min (analytical conditions: SMD-FA05-3).

Stage 1-3.

tert-Butyl-3-(2,2-dimethoxyethylcarbamoylamino)-2-(3,5-dimethylphenyl)-6,7-dihydro-4Hpyrazolo[4,3-c]pyridine-5-carboxylate (compound 1f).

To a solution of compound 1d (2.53 g, 7.39 mmol) in pyridine (7.39 ml) obtained in step 1-2 was added 2-isocyanato-1,1-dimethoxyethane (compound 1e, 1.94 g, 14.8 mmol), and the mixture was stirred at room temperature. After 3 hours and 15 minutes, diethylamine (1.08 g, 14.8 mmol) was added and the mixture was stirred at room temperature for 5 minutes, then water (50.6 ml) was added and the resulting mixture was stirred at room temperature for 20 minutes. . The reaction mixture, which became a suspension, was filtered and the resulting solid was washed with water (12.7 ml) then dried under reduced pressure to give the title compound 1f (3.20 g, 91% yield) in as a pale yellow solid.

LC/MS mass spectrometry: m/z 474 ([M+H]+).

LC/MS retention time: 0.78 min (analytical conditions: SQD-FA05-1).

Stage 1-4.

3-[2-(3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1H-imidazol-2-one (compound 1g).

Formic acid (3.84 mL, 100 mmol) was added to compound 1f (158 mg, 0.334 mmol) obtained in steps 1-3 and the resulting mixture was stirred at room temperature for 21 hours. The reaction mixture was evaporated under reduced pressure and added toluene and solvent were evaporated under reduced pressure. Dichloromethane (1 ml) was added to the residue to dissolve it, and then a solution of hydrogen chloride (4M dioxane solution, 0.835 ml, 3.34 mol) was added at room temperature. The reaction mixture was evaporated under reduced pressure. Toluene was added and the solvent was evaporated under reduced pressure to give the crude product (176 mg) of the title compound 1g.

LC/MS mass spectrometry: m/z 310 ([M+H]+).

LC/MS retention time: 0.39 min (analytical conditions: SQD-FA05-3).

Stage 1-5.

4-Bromo-2-ethyl-3-methylpyridine (compound 1i).

A solution of 4-bromo-2,3-dimethylpyridine (compound 1 h, 7.05 g, 37.9 mmol) in THF (75.0 ml) was cooled to -78°C and then 1.11 M lithium diisopropylamide solution was added slowly in a mixture of n-hexane-THF (35.8 ml, 39.8 mmol). The reaction mixture was stirred at -78°C for 5 minutes and then iodomethane (2.84 ml, 45.5 mmol) was added. The reaction mixture was stirred at -78°C for 5 minutes and slowly warmed to room temperature. The reaction mixture was then stirred for 30 minutes and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate) and the title compound 1i (6.98 g, 92% yield) was obtained as an orange oil.

LC/MS mass spectrometry: m/z 200 ([M+H]+).

LC/MS retention time: 0.38 min (analytical conditions: SQD-FA05-3).

Stage 1-6.

Ethyl 5-bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]indole-2-carboxylate (compound 11).

From a solution of ethyl 5-bromo-1-(cyanomethyl)indole-2-carboxylate (compound 1j, 3.60 g, 11.7 mmol) and (4R)-4-methyl-1,3,2-dioxαthiolαn-2, 2-dioxide (compound 1k, 4.86 g, 35.2 mmol) in N,N'dimethylpropyleneurea (117 ml) was removed from air under reduced pressure, then the vessel was filled with nitrogen and the mixture was cooled to 0°C. Under a nitrogen atmosphere, a 1.0 M solution of potassium bis(trimethylsilyl)amide in THF (46.9 mL, 46.9 mmol) was slowly added dropwise. The reaction mixture was stirred at 0°C for 2.5 hours, then formic acid (5.30 ml, 141 mmol) was added and extracted using hexane/ethyl acetate (1:3). The organic layer was washed three times with water, twice with a saturated aqueous sodium hydrogen carbonate solution and once with an aqueous saturated sodium chloride solution, and then dried with sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:19 to 1:4) to obtain the title compound 11 (1.70 g, 42% yield) as a white solid. . LC/MS mass spectrometry: m/z 347 ([M+H]+).

LC/MS retention time: 0.69 min (analytical conditions: SQD-AA50-1).

Stage 1-7.

Ethyl 1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-5-(2-ethyl-3-methylpyridin-4-yl)indole-2carboxylate (compound 1m).

From a suspension of compound 11 (2.70 g, 7.78 mmol) obtained in steps 1-6 in dioxane (44 ml), 4,4,4',4',5,5,5',5'- Octamethyl-2,2'-bis(1,3,2-dioxaborolane) (2.17 g, 8.55 mmol) and potassium acetate (1.15 g, 11.7 mmol) were removed under reduced pressure and then the vessel was filled with nitrogen. Under a nitrogen atmosphere, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex and dichloromethane (1.29 g, 1.56 mmol) were added and the mixture was stirred at 100°C for 3 hours. After cooling the solution to At room temperature, 4-bromo-2-ethyl-3-methylpyridine (compound 1i, 2.33 g, 11.7 mmol), sodium carbonate (2.47 g, 23.3 mmol) and water (7.4 ml), and then air was removed from the solution under reduced pressure. The vessel was filled with nitrogen and the solution was stirred at 100°C for 2 hours. The solution was cooled to room temperature and then water (5.4 ml) and N-acetylcysteine (0.635 g, 3.89 mmol) were added. The mixture was stirred for 0.5 hour. The reaction mixture was extracted with ethyl acetate and the organic layer was washed once with brine, and then dried using sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane 1:19 to 2:3) to give the title compound 1m (2.92 g, 97% yield) as a pale yellow viscous product.

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LC/MS mass spectrometry: m/z 388 ([M+H]+).

LC/MS retention time: 1.06 min (analytical conditions: SQD-AA05-2).

Stage 1-8.

Ethyl 5-(2-ethyl-3-methylpyridin-4-yl)-1 -[(1 S,2S)-2-methyl-1 -(5 -oxo-4H-1,2,4-oxadiazol-3 yl )cyclopropyl]indole-2-carboxylate (compound 1n).

To a solution of compound 1m (0.225 g, 0.581 mmol) obtained in steps 1-7 in dimethyl sulfoxide (DMSO) (2.9 ml) was added a 50% aqueous solution of hydroxylamine (0.356 ml, 5.81 mmol), and the mixture stirred at room temperature for 17 hours. Ethyl acetate (50 ml) was added, the mixture was washed with water (10 ml) and saturated aqueous sodium chloride (10 ml), and then dried with magnesium sulfate. After filtering the mixture, the filtrate was evaporated under reduced pressure and the resulting residue was dissolved in DMSO (1.9 ml). Carbonyldiimidazole (188 mg, 1.16 mmol) and 1,8diazabicycloundec-7-ene (0.219 mL, 1.45 mmol) were then added and the resulting mixture was stirred at room temperature for 0.5 h. Formic acid was added to the mixture and then purified by reverse phase chromatography (acetonitrile/water, 0.1% formic acid) to give the title compound 1n (169 mg, 65% yield) as a white powder.

LC/MS mass spectrometry: m/z 447 ([M+H]+).

LC/MS retention time: 0.80 min (analytical conditions: SMD-FA05-3).

Stage 1-9.

5-(2-ethyl-3-methylpyridin-4-yl)-1 -[(1 S,2S)-2-methyl-1 -(5-oxo-4H-1,2,4-oxadiazol-3yl)cyclopropyl ]indole-2-carboxylic acid (compound 1o).

To a solution of compound 1n (3.61 g, 8.08 mmol) obtained in steps 1-8 in DMSO (40 ml) was added 2M sodium hydroxide solution (10.1 ml, 20.2 mmol) and the mixture was stirred at room temperature for 1.5 hours. Formic acid was added to the mixture and then purified by reverse phase chromatography (acetonitrile/water, 0.1% formic acid) to obtain the title compound 1o (3.38 mg, 100% yield) as a white powder.

LC/MS mass spectrometry: m/z 419 ([M+H]+).

LC/MS retention time: 0.83 min (analytical conditions: SQD-AA05-2).

Stage 1-10.

3-[(1S,2S)-1-[2-[2-(3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo [4,3c]pyridin-5-carbonyl]-5-(2-ethyl-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4oxadiazol-5-one (connection 1p).

To a solution of compound 1g (1.25 g, 3.61 mmol) obtained in step 1-4, compound 1o (1.59 g, 3.80 mmol) obtained in step 1-9 and [dimethylamino(triazolo[4 Diisopropylethylamine (3.15 ml, 18.1 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was directly purified by reverse phase column chromatography (acetonitrile/water, 0.1% formic acid) and the title compound 1p (2.44 g, 95% yield) was obtained as a light brown foam.

LC/MS mass spectrometry: m/z 710 ([M+H]+).

LC/MS retention time: 0.85 min (analytical conditions: SMD-FA05-3).

Stage 1-11.

3-[(1S,2S)-1-[2-[2-(3,5-dimethylphenyl)-3-[3-(1-indazol-5-yl)-2-oxoimidazol-1-yl]-6 ,7-dihydro-4Hpyrazolo[4,3-c]pyridin-5-carbonyl]-5-(2-ethyl-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]4H-1, 2,4-oxadiazol-5-one (compound 1).

To a suspension of compound 1p (20 mg, 0.028 mmol) obtained in steps 1-10, 5-bromo-1methylindazole (compound 1q, 11.9 mg, 0.056 mmol), (1S,2S)-1-N, 2-N -dimethylcyclohexane-1,2-diamine (1.6 mg, 0.011 mmol) and potassium carbonate (11.7 mg, 0.085 mmol) in N-methylpyrrolidone (0.188 ml) was added copper (I) iodide (1.1 mg, 0 0056 mmol) at room temperature, and the mixture was stirred under nitrogen at 130°C for 3 hours. The reaction mixture was purified by reverse phase chromatography on silica gel (acetonitrile/water, 0.1% formic acid) and the title compound 1 (17 .2 mg, yield 73%) was obtained in the form of a light brown foam.

LC/MS mass spectrometry: m/z 840 ([M+H]+).

LC/MS retention time: 1.12 min (analytical conditions: SMD-TFA05-3).

Examples 2-50.

A step similar to steps 1-11 of example 1 was carried out using a combination of the 2-oxoimidazole compound shown in table. 2-2, and the halide indicated in table. 2-3 below, as well as the corresponding reagent and compound of Example 2-50 listed in table. 2-1 were obtained by the following reaction.

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Chemical formula 18

Table 2-1

Examples of compounds obtained from compound 2 to compound 50

Example No. Structure Compound Analytical conditions Retention time lc/m s (min.) LC/MS mass spectrum ometry (m/z) 2 Ds Dssh 3-[(l S, 28)-1-[5-(2-ethyl-3methylpyridin-4-yl)-2-[2(4-fluoro-3,5dimethylphenyl)-3 -[3 -(1 methylind azole -5 -yl)-2oxoimidazol-1 -yl]-6,7dihydro-4H-pyrazolo[4,3 c]pyridin-5carbonyl]in ol-1 -yl]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5 -He SMDTFA05-3 1.15 858 ([M+HD 3 Yes- DOS 3-[(18.28)-1-[5-(2-ethyl-3methylpyridin-4-yl)-2-[2(4-fluoro-3,5dimethylphenyl)-3 -[3 -(3 methyl-1 ,2-benzothiazol-6yl)-2-oxoimidazol-1 yl] -6,7 - dihydro-4Hpyrazolo[4,3-c]pyridin5 -carbonyl] ind o l-1 -yl] 2-methylcyclopropyl]-4H1, 2,4-oxadiazol-5-one SMDTFA05-3 1.22 875 ([m+nH) 4 D ό- 3-[(18.28)-1-[5-(2-ethyl-3methylpyridin-4-yl)-2-[2(4-fluoro-3,5dimethylphenyl)-3 -[3 -(3 fluoro-4 -methoxyphenyl)-2oxoimidazol-1 -yl]-6,7dihydro-4H-pyrazolo[4,3 c]-pyridin-5carbonyl]indol-1 -yl]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-3 1.21 852 ([m+nH) 5 g / (_ Vu . '-O \—7 tj /XX ^m - ^V A 3-[(lS,2S)-l-[2-[3-[3-(l,3dimethylindazol-6-yl)-2oxoimidazol-1 -yl]-2-(4fluoro-3,5-dimethylphenyl)6, 7-dihydro-4Hpyrazolo[4,3-c]pyridin5 -carbonyl] - 5 -(2-ethyl-3 methylpyridin-4yl)indol-1-yl]- 2- methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMD- TFA05-3 1.18 872 ([m+nH) 6 DoA Hya 3-[(18.28)-1-[2-[2-(4-fluoro3,5-dimethylphenyl)-3 - [3 [ 1 -(2-hydroxy-2methylpropyl)in d azol-5 yl]-2 -oxoimidazol-1yl]-6,7 - dihydro-4Hpyrazolo[4,3-c]pyridin5-carbonyl] - 5 -(2-methoxy3-methylpyridin-4yl)indol-1-yl]-2methylcyclopropyl]-4H1,2 ,4-oxadiazol-5-one SMD- TFA05-2 1.40 919 ([M+NG)

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7 5 3-[(lS,2S)-l-[5-(2,2- dimethylmorpholin-4-yl)2-[2-(4-fluoro-3,5- dimethylphenyl)-3-[3-[1-(2methoxyethyl)indazol-5 yl]-2-oxoimidazol-1 yl]-6,7-dihydro-4Hpyrazolo[4,3 -с]pyridin5 -carbonyl] indole-1 - yl]2-methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-3 1.32 896 ([M+H] ⁺ ) 8 O Δ o XX' A Χ-βχ 3-[(18.28)-1-[2-[2-(4-fluoro3,5-dimethylphenyl)-3 - [2oxo-3 -[ 1 -[(3K)-oxolan-3 yl]indazol-5yl ]imidazol-1-yl]-6,7d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5(oxan-4-yl)in ol-1 -yl] 2-methylcyclopropyl] -4H1 ,2,4-oxadiazol-5-one SMDTFA05-2 1.38 879 ([M+H] ⁺ ) 9 9 9 ΑΧ Ν-[4-[3-[2-(4-φτορ-3,5dimethylphenyl)-5-[ 1 [(18,28)-2-methyl-1-(5oxo-4H-1,2,4-oxadiazole3 -yl)cyclopropyl]-5 (oxan-4-yl)indol-2carbonyl]-6,7-dihydro4H-pyrazolo[4,3c]pyrid in-3 -yl]-2oxoimidazol-1 -yl]-2methoxyphenyl]-M -(3methoxypropyl)acetamide SMDTFA05-2 1.33 929 ([M+H] ⁺ ) 10 // ω 3-[(18.28)-1-[2-[2-(4-fluoro3,5-dimethylphenyl)-3 - [2oxo-3-[1-(2,2,2- trifluoroethyl)ind azol-5 yl]imidazol-1-yl]-6,7d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5(oxan-4-yl)ind ol-1 -yl ]2-methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-2 1.47 891 ([M+H] ⁺ ) eleven D<AG ’d 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)3-[3-[1-(2- methoxyethyl)indazol-5 yl]-2-oxoimidazol-1 yl]-4-methyl-6,7-d ihydro4H-pyrazolo[4,3c]pyridin-5-carbonyl]-5(2-methoxy-3methylpyridin-4yl) indol-1-yl]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-2 1.49 919 ([M+H] ⁺ )

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12 9 h Ά-Ή l 3-[(lS,2S)-l-[2-[(4S)-2-(4φτορ-3,5-d imethylphenyl)4-methyl-3-[3-(1- methylind azol-5 -yl)-2oxoimid azol-1 -yl]-6,7 d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5(2-methoxy-3- methylpyridin-4-yl)indol -1-yl]-2- methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.45 874 ([M+H] ⁺ ) 13 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)3 - [3 -[ 1 -(2-hydroxy-2methylpropyl)indazol-5yl] -2-oxoimidazol-1 yl]-4-methyl-6,7-d ihydro4H-pyrazolo[4,3c]pyridin-5-carbonyl]-5(2-methoxy-3methylpyridin-4yl)indol-1 -yl]- 2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.42 932 ([M+H] ⁺ ) 14 ^χ^Χν* _z |Xb 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)4-methyl-3 -[2-oxo-3 -[ 1 [(38) -oxolan-3yl]indazol-5yl]imidazol-1-yl]-6,7d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5(3-fluoro-2-methylpyridin4-yl)indole -1 -yl]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.15 918 ([M+H] ⁺ ) 15 χ. A'?'^ /,χ 3-[(lS,2S)-l-[5-[2(dimethylamino)-3 methylpyridin-4-yl]-2[(48)-2-(Chfluoro-3,5dimethylphenyl)-4-methyl3 - [3 -(1 -methylind azol-5 yl)-2-oxoimid azol-1 yl]-6,7-dihydro-4Hpyrazolo[4,3 -с]pyridin5 -carbonyl] indol-1 -yl] 2-methylcyclopropyl] -4H1 ,2,4-oxadiazol-5-one SQDFA05-1 0.75 887 ([M+H] ⁺ )

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16 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)3-(3-(1-(2methoxyethyl)indazol-5 yl]-2- oxoimidazol-1 yl]-4-methyl-6,7-d ihydro4H-pyrazolo[4,3c]pyridin-5-carbonyl]-5(oxan-4-yl)indol 1-yl]2-methylcyclopropyl] -4H1, 2,4-oxadiazol-5-one SMDTFA05-2 1.45 882 ([M+H] ⁺ ) 17 3-((1 S,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)4-methyl-3-[3-[1-((3- methyloxetane-3 - yl)methyl]indazol-5-yl]-2oxoimid azol-1-yl]-6,7 d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5(oxan-4-yl)indole -1-yl]2-methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-2 1.45 908 ([M+H] ⁺ ) 18 ν_Λα / y > l=/^ / '.^d ' ¹ 3-((1 S,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)4-methyl-3-[3-(3-methyl1,2-benzothiazol- 6-yl)-2oxoimid azol-1-yl]-6,7 d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5(oxan-4-yl)indol -1-yl]2 -methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.50 854 ([M+H] ⁺ ) 19 X m - aQxd ^Z _n Ah 3-((1 S,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)3-[3-[4-(2- hydroxyethoxy)-3 methylphenyl]-2oxoimidazol-1 -yl]-4methyl-6,7-dihydro-4Hpyrazolo[4,3 -c]pyridin5 -carbonyl] - 5 -(oxan-4 yl)indol-1 -yl]- 2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.36 857 ([M+H] ⁺ ) 20 4 3-((1 S,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)3-[3-[4-(1-hydroxy-2methylpropan-2-yl )oxy-3 methoxyphenyl]-2oxoimidazol-1 -yl]-4methyl-6,7-dihydro-4Hpyrazolo[4,3 -c]pyridin5 -carbonyl] - 5 -(oxan-4 yl)indol-1 -yl]- 2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.40 901 ([M+H] ⁺ )

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21 b- Cj s^sno / _b .LCHN A. 3-[(lS,2S)-l-[2-[(4S)-3-[3(4-ethylsulfonylphenyl)2-oxoimidazol-1 -yl]-2(4-fluoro-3,5dimethylphenyl)-4- methyl6,7-dihydro-4Hpyrazolo[4,3-c]pyridin5-carbonyl]-5-(oxan-4yl)indol-1-yl]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.37 875 ([M+H] ⁺ ) 22 ^yy ''D 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)4-methyl-3-[2-oxo-3-[1[(38) -oxolan-3yl]indazol-5yl]imidazol-1-yl]-6,7d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5(oxan-4-yl)ind ol-1 - yl]2-methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.40 893 ([M+H] ⁺ ) 23 j>Jz^xpO Cj' 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)3-[3-(4-fluoro-1methylindazol-5 -yl)-2oxoimidazole -1 -yl]-4methyl-6,7-dihydro-4Hpyrazolo[4,3 -с]pyridin5 -carbonyl] -5 -(oxan-4yl)indol-1 yl]-2- methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.41 855 ([M+H] ⁺ ) 24 _x ^Oe^o · 'A 3-[(lS,2S)-l-[2-[(4S)-3-[3(1,1-dimethyl-3,4dihydroisochromen-6-yl)2-oxoimidazol-1 -yl]-2(4 -fluoro-3,5dimethylphenyl)-4-methyl6,7-dihydro-4Hpyrazolo[4,3 -с]pyridin5 -carbonyl]-5 -(oxan-4yl)indol-1 -yl]-2- methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.52 867 ([M+H] ⁺ ) 25 _ζ £Α^ΣΗ3 <4 3-[(lS,2S)-l-[2-[(4S)-3-[3[4-[6- (dimethylamino)pyrimidin n-4-yl]-3 -methylphenyl]-2oxoimid azol-1 yl]-2-(4fluoro-3,5-d imethylphenyl)4-methyl-6,7-dihydro-4Hpyrazolo[4,3 -c]pyridin5 -carbonyl]-5 -(oxan-4yl)indol-1 -yl]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.12 918 ([M+H] ⁺ )

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26 Hl.X)X ' A 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3,5-dimethylphenyl)3-[3-[l-(2- fluoroethyl)indazol-5-yl] 2-oxoimidazol-1-yl]-4methyl-6,7-dihydro-4Hpyrazolo[4,3-c]pyridin5-carbonyl] - 5 -(oxan-4yl)indole 1- ill]-2- methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.39 869 ([M+H] ⁺ ) 27 Dd Ύ<Y 3-[(lS,2S)-l-[2-[(4S)-2-(4- fluoro-3,5-d and methylphenyl)3-[3-(6-fluoro-1- methylind azol-5 -yl)-2oxoimidazol-1 -yl]-4methyl-6,7-dihydro-4Hpyrazolo[4,3 -с]pyridin5 -carbonyl] - 5 -(oxan-4 yl)indol-1 yl]- 2- methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.39 855 ([M+H] ⁺ ) 28 a ^j γ ji jOo o. ^u X^-' 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)3-[3-[4-fluoro-1-(2,2,2trifluoroethyl) ind azol-5 yl]-2-oxoimidazol-1 yl]-4-methyl-6,7-d ihydro4H-pyrazolo[4,3c]pyridin-5-carbonyl]-5(oxan-4-yl) ind ol- 1 -yl] 2-methylcyclopropyl] -4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.44 923 ([M+H] ⁺ ) 29 >^ZHD Af 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)3-[3-[4-fluoro-1-[(3methyloxetan-3 yl) methyl]indazol-5-yl]-2oxoimidazol-1 -yl]-4methyl-6,7-dihydro-4Hpyrazolo[4,3 -c]pyridin5 -carbonyl] - 5 -(oxan-4 yl)indol-1 -yl ]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.40 925 ([M+H] ⁺ ) thirty XX a | X 2 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)3-[3-[4-fluoro-1-(2hydroxy-2methylpropyl)indazol- 5yl]-2-oxoimidazol-1 yl]-4-methyl-6,7-d ihydro4H-pyrazolo[4,3c]pyridin-5-carbonyl]-5(oxan-4-yl)in ol-1 -yl] 2-methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMD- TFA05-1 1.36 913 ([M+H] ⁺ )

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31 3-[(lS,2S)-l-[5-[(4S)-2,2dimethyloxan-4-yl]-2[(48)-2-(4-fluoro-3,5dimethylphenyl)-3-[3 -[1-(2methoxyethyl)indazol-5 yl]-2-oxoimidazol-1 yl]-4-methyl-6,7-d ihydro4H-pyrazolo[4,3c]pyridin-5carbonyl]indol-1 -yl]-2methylcyclopropyl ]-4H1,2,4-oxadiazol-5-one SMDTFA05-2 1.48 909 ([M+H] ⁺ ) 32 AL ό ν -А ^g > P ХМ ' V n 3-[(lS,2S)-l-[5-[(4S)-2,2dimethyloxan-4-yl]-2[(48)-3-[3-(1,3-dimethyl-2oxobenzimidazol-5 - yl)2-oxoimidazol-1 -yl]-2(4-fluoro-3,5dimethylphenyl)-4-methyl6,7-dihydro-4Hpyrazolo[4,3 -с] pyridin5 -carbonyl] indol-1 -yl] 2- methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.39 895 ([M+H] ⁺ ) 33 & . сУа ⁴ ^ _ζ ^Μ·Μ 3-[(lS,2S)-l-[5-[(4S)-2,2dimethyloxan-4-yl]-2[(48)-2-(4-fluoro-3,5dimethylphenyl)-3-[3 -[1-(2methoxyethyl)-3 -methyl-2oxobenzimidazol-5 -yl] 2-oxoimidazol-1 -yl]-4methyl-6,7-dihydro-4Hpyrazolo[4,3 -с]pyridin5 -carbonyl] indole-1 -yl]2-methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.41 939 ([M+H] ⁺ ) 34 Μ'Ή? 3-[(lS,2S)-l-[5-[(4S)-2,2dimethyloxan-4-yl]-2[(48)-2-(4-fluoro-3,5dimethylphenyl)-3 -[3 -(1Nindazol-5-yl)-2oxoimidazol-1-yl]-4methyl-6,7-dihydro-4Hpyrazolo[4,3 -c]pyridin5-carbonyl]indol-1-yl]2-methylcyclopropyl]-4H1,2 ,4-oxadiazol-5-one SMDTFA05-1 1.37 851 ([M+H] ⁺ )

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35 'a 3-[(lS,2S)-l-[5-[(4S)-2,2dimethyloxan-4-yl]-2[(48)-2-(4-fluoro-3,5dimethylphenyl)-3-[3 -[4fluoro-1-(2,2,2trifluoroethyl)ind azol-5 yl]-2-oxoimidazol-1 yl]-4-methyl-6,7-d ihydro4Hpyrazolo[4,3c]pyridine-5carbonyl]indole-1 -yl]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.51 951 ([M+H] ⁺ ) 36 I-λ Γ; %d 'Ρρ 3-[(lS,2S)-l-[5-[(4S)-2,2dimethyloxan-4-yl]-2[(48)-2-(4-fluoro-3,5dimethylphenyl)-3-[3 -[4fluoro-1-(2methoxyethyl)indazol-5 yl]-2-oxoimidazol-1 yl]-4-methyl-6,7-d ihydro4H-pyrazolo[4,3c]pyridin-5carbonyl]indol-1 -yl] -2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.46 927 ([M+H] ⁺ ) 37 Ρ- Λ ^Λ αλΑΛΑ Cj ^vJ ' A ^d / Λ. M. 3-[(lS,2S)-l-[5-[(4S)-2,2dimethyloxan-4-yl]-2[(48)-2-(4-fluoro-3,5dimethylphenyl)-3-[3 -[4fluoro-1 -[(3 -methyloxetan3-yl)methyl]indazol-5-yl]2-oxoimidazol-1 -yl]-4methyl-6,7-dihydro-4Hpyrazolo[4,3 -c]pyridin5 -carbonyl ] indol-1 -yl] 2-methylcyclopropyl] -4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.46 953 ([M+H] ⁺ ) 38 (Τ^Λ'Ά” be ^r e 3-[(lS,2S)-l-[5-[(4S)-2,2dimethyloxan-4-yl]-2[(48)-2-(4-fluoro-3,5dimethylphenyl)-3-[3 -[4fluoro-1 -(2-hydroxy-2methylpropyl)indazol-5yl]-2-oxoimidazol-1 yl]-4-methyl-6,7-d ihydro4H-pyrazolo[4,3c]pyridine-5carbonyl]indole-1 -yl]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.42 941 ([M+H] ⁺ )

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39 ^Z <4 3-[(lS,2S)-l-[5-[(4S)-2,2dimethyloxan-4-yl]-2[(48)-2-(4-φτορ-3,5dimethylphenyl)-4-methyl3 - [3 -(2-methyl-3-oxo-1,4dihydroisoquinolin-6yl)-2-oxoimid azol-1 yl]-6,7-dihydro-4Hpyrazolo[4,3 -c]pyridin5 -carbonyl]indole-1 - yl]2-methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.33 894 ([M+H] ⁺ ) 40 I'm Ό Νύ 3-[(lS,2S)-l-[5-[(4S)-2,2dimethyloxan-4-yl]-2[(48)-2-(4-fluoro-3,5dimethylphenyl)-3-[3 -[4fluoro-1 -[(3 8)-oxolan-3 yl]indazol-5-yl]-2oxoimidazol-1 -yl]-4methyl-6,7-dihydro-4Hpyrazolo[4,3 -с]pyridin5 -carbonyl ] indol-1 -yl] 2-methylcyclopropyl] -4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.46 939 ([M+H] ⁺ ) 41 L 'L ό X ¹ ? ⁰ Λ 3-[(lS,2S)-l-[2-[(4S)-2-(4- fluoro-3,5-d and methylphenyl)3-[3-(4-fluoro-1- methylind azol-5 -yl)-2oxoimidazol-1 -yl]-4methyl-6,7-dihydro-4Hpyrazolo[4,3 -c]pyridin5-carbonyl]-5-[(28,4S)-2methyloxan-4-yl ]indol-1 yl]-2- methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.44 869 ([M+H] ⁺ ) 42 t° 9 ^{s; : 1} ρ 3-[(lS,2S)-l-[2-[(4S)-2-(4chloro-3,5-d imethylphenyl)3-[3-[4-fluoro-1-(2,2,2- trifluoroethyl)ind azol-5 yl]-2-oxoimidazol-1 yl]-4-methyl-6,7-d ihydro4H-pyrazolo[4,3c]pyridin-5-carbonyl]-5[(4 8)-2, 2-dimethyloxan-4yl]indol-1-yl]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.56 967 ([M+H] ⁺ )

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43 MW ο ρ 3-[(lS,2S)-l-[2-[(4S)-2-(4chloro-3,5-d imethylphenyl)3-[3-[4-φτορ-1-(2methoxyethyl)indazol-5 yl ]-2-oxoimidazol-1 yl]-4-methyl-6,7-dihydro4H-pyrazolo[4,3c]pyridin-5-carbonyl]-5[(4 S)-2,2-dimethyloxan-4yl]indol- l-yl]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.53 943 ([M+H] ⁺ ) 44 X „U ΧάΧ ΧΧζΖ 3-[(lS,2S)-l-[2-[(4S)-2-(4chloro-3,5-d imethylphenyl)3-[3-[4-fluoro-1-(2,2,2trifluoroethyl) ind azol-5 yl]-2-oxoimidazol-1 yl]-4-methyl-6,7-dihydro4H-pyrazolo[4,3c]pyridin-5-carbonyl]-5(oxan-4-yl) ind ol-1 -yl]2-methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.50 939 ([M+H] ⁺ ) 45 J A nA A-/ ' 3-[(lS,2S)-l-[2-[(4S)-2-(4chloro-3,5-d imethylphenyl)3-[3-[4-fluoro-1-(2- methoxyethyl)indazol-5 yl]-2-oxoimidazol-1 yl]-4-methyl-6,7-dihydro4H-pyrazolo[4,3c]pyridin-5-carbonyl]-5(oxan-4-yl)indol- 1 -yl] 2-methylcyclopropyl] -4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.46 915 ([M+H] ⁺ ) 46 « ζ Λ wv /W X: 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3-methylphenyl)-3 - [3 [4-fluoro-1-(2,2,2trifluoroethyl)ind azol- 5 yl]-2-oxoimidazol-1 yl]-4-methyl-6,7-dihydro4H-pyrazolo[4,3c]pyridin-5-carbonyl]-5(oxan-4-yl)in ol-1 -yl] 2-methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.39 909 ([M+H] ⁺ ) 47 \ Τ φ χΧ 3-[(lS,2S)-l-[2-[(4S)-3-[3[4-ft°R-G(2methoxyethyl)indazol-5 yl]-2-oxoimidazol-1 yl]-2- (4-fluoro-3methylphenyl)-4-methyl-6,7 d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5(oxan-4-yl)in ol-1 -yl] 2 -methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.34 885 ([M+H] ⁺ )

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48 n A / CHA La 3-[(lS,2S)-l-[5-[(4S)-2,2dimethyloxan-4-yl]-2[(48)-3-[3-[4-fluoro-1-(2methoxyethyl)indazole -5 yl]-2-oxoimidazol-1 yl]-2-(4-fluoro-3methylphenyl)-4-methyl-6,7 dihydro-4H-pyrazolo[4,3 c]pyridin-5carbonyl]indol-1 -yl ]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.41 913 ([M+H] ⁺ ) 49 n, 3-[(lS,2S)-l-[2-[(4S)-3-[3(4-chloro-1-methylindazol5 -yl)-2-oxoimid azol-1 yl]-2-(4-fluoro -3methylphenyl)-4-methyl-6,7 d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5[(4 S)-2,2-dimethyloxan-4yl]indol-l-yl ]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-1 1.42 885 ([M+H] ⁺ ) 50 δ. 3-[(lS,2S)-l-[5-[(4S)-2,2dimethyloxan-4-yl]-2[(48)-2-(4-fluoro-3methylphenyl)-4-methyl-3 [ 3 -(1 -methylindazol-5 -yl)2-oxoimidazol-1 -yl]-6,7d ihydro-4H-pyrazolo[4,3 c]pyridin-5carbonyl]indol -1-yl]-2methylcyclopropyl]-4H1, 2,4-oxadiazol-5-one SMDTFA05-1 1.37 851 ([M+H] ⁺ )

Connections in the table. 2-1 have rotational isomers, and as an example, ^{the 1} H-NMR compound of an example compound of Example 2 is given below.

Rotamer A.

¹ H-NMR (600 MHz, CDCl ₃ ) δ: 11.29 (1H, s), 8.40 (1H, d, J=5.2 Hz), 7.93 (1H, s), 7.74 (1H, d, J=1.5 Hz), 7.70 (1H, d, J=8.6 Hz), 7.56 (1H, s), 7.45 (1H, dd, J=9, 0, 1.5 Hz), 7.38 (1H, d, J=9.0 Hz), 7.28 (1H, m), 7.14 (1H, d, J=5.2 Hz), 7 .04 (2H, d, J _No. =5.9 Hz), 6.82 (1H, s), 6.59 (1H, d, J = 3.0 Hz), 6.08 (1H, d, J =3.0 Hz), 4.96 (1H, d, J=16.0 Hz), 4.92 (1H, d, J=16.0 Hz), 4.69 (1H, ddd, J=13 ,l, 4.4, 4.4 Hz), 4.06 (3H, s), 3.75 (1H, ddd, J=13.1, 9.5, 5.0 Hz), 3.07 ( 2H, m), 2.97 (2H, kV, J=7.6 Hz), 2.26 (3H, s), 2.25 (6H, s), 1.88 (1H, s), 1, 51 (2H, m), 1.37 (3H, t, J=7.6 Hz), 1.17 (3H, d, J=5.6 Hz).

Rotamer V.

¹ H-NMR (600 MHz, CDCl3) δ: 11.29 (1H, s), 8.44 (1H, d, J=5.2 Hz), 8.04 (1H, s), 7.90 ( 1H, d, J=l,4 Hz) 7.73 (1H, d, J=8.8 Hz), 7.63 (1H, dd, J=9.0, 1.4 Hz), 7.60 (1H, s), 7.51 (1H, d, J=9.0 Hz), 7.30 (1H, m), 7.20 (1H, d, J=5.2 Hz), 7.11 (2Н, d, J _№ =6.0 Hz), 6.81 (1H, s), 6.71 (1H, d, J=3.0 Hz), 6.22 (1H, d, J=3 ,0 Hz), 5.24 (1H, d, J=16.3 Hz), 4.64 (1H, d, J=16.3 Hz), 4.45 (1H, ddd, J=13.5 , 4.6, 4.0 Hz), 4.12 (3H, s), 3.87 (1H, ddd, J=13.5, 10.2, 3.8 Hz), 3.17 (1H, ddd, J=15.5, 10.2, 4.6 Hz), 3.02 (1H, m), 3.00 (2H, kV, J=7.6 Hz), 2.30 (3H, s ), 2.28 (6H, s), 1.96 (1H, dd, J=6.0 Hz), 1.64 (1H, m), 1.58 (1H, dd, J=9.4, 6.0 Hz), 1.39 (3H, t, J=7.6 Hz), 1.19 (3H, d, J=6.1 Hz).

- 36 044109

Table 2-2

Used 2-oxoimidazole compounds

Example No. 2-oxoimidazole compound Compound Analytical conditions LC/MS retention time (min.) LC/MS mass spectrometry (m/z) 2-5 (2g connection) tv A / [>. ¹ jA '— 3-[(18.28)-1-[5-(2-ethyl-3methylpyridin-4-yl)-2-[2(4-fluoro-3,5- d methylphenyl)-3 -(2-oxo1 H-imidazol-3 -yl)-6,7 d ihydro-4H-pyrazolo[4,3 c]pyridin-5carbonyl]indol-1 -yl]-2methylcyclopropyl]-4H1, 2, 4-oxadiazol-5-one SMD-FA05-3 0.86 728 ([M+H] ⁺ ) 6 (Connection 6i) Ag A DA-Ln CHA AJ ^/ 3-[(18.28)-1-[2-[2-(4-fluoro3,5-d imethylphenyl)-3-(2oxo-1H-imidazol-3-yl)6,7-dihydro-4Hpyrazolo[ 4,3 -c]pyridin5 -carbonyl]-5 -(2-methoxy3 -methylpyridin-4yl)indol-1 -yl]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMD-FA05-2 1.33 730 ([M+H] ⁺ ) 7 (Connection 7c) tv AXA. L.J. L· 3-[(lS,2S)-l-[5-(2,2- dimethylmorpholin-4-yl)2-[2-(4-fluoro-3,5- d methylphenyl)-3 -(2-oxo1 H-imidazol-3 -yl)-6,7 d ihydro-4H-pyrazolo[4,3 c]pyridin-5carbonyl]indol-1 -yl]-2methylcyclopropyl]-4H1, 2,4 oxadiazol-5-one SMD-FA05-3 1.22 722 ([M+H] ⁺ )

- 37 044109

δ- 10 (Connection 8c) 3-[(18.28)-1-[2-[2-(4-φτορ3,5-d imethylphenyl)-3 -(2oxo-1 Η-imidazol-3 -yl)6,7-dihydro-4Hpyrazolo[ 4,3 -c]pyridin5 -carbonyl]-5 -(oxan-4yl)indol-1 -yl]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMD-FA05-1 1D9 693 ([M+H] ⁺ ) eleven- 13 (Connection by Him) Ur l LA-Am! 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)4-methyl-3 -(2-oxo-1Nimide azol-3-yl)- 6,7d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5(2-methoxy-3methylpyridin-4yl)indol-1 -yl]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5 -He SMD-FA05-1 1.33 744 ([M+H] ⁺ ) 14 (Compound 14d) & Ν-Ν η ,ΛΑ-Ν' 'NH SA'·. ΆΛνη f ' O 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)4-methyl-3 -(2-oxo-1Nimide azol-3-yl)- 6,7d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5(3-fluoro-2-methylpyridin4-yl)indol-1 -yl]-2methylcyclopropyl]-4H1,2,4-oxadiazole -5-he SMD-FA05-1 1.15 732 ([M+H] ⁺ ) 15 (Connection 15d) Ur A 1Αη ^α νη υί ^υ ' Ά ν~. ' .Λνη ^ζ ν- oD ' ο 3-[(lS,2S)-l-[5-[2- (dimethylamino)-3 methylpyridin-4-yl]-2[(48)-2-(4-fluoro-3,5dimethylphenyl)-4-methyl3 -(2-oxo-1 H-imidazol-3 yl)-6, 7-dihydro-4Hpyrazolo[4,3 -с] pyridin5 -carbonyl] indol-1 -yl] 2-methylcyclopropyl] -4H1,2,4-oxadiazol-5-one SQD-FA05-1 0.67 757 ([M+H] ⁺ ) 16- thirty (Compound 16a) Ur Ν-Ν and Ν4 C 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)4-methyl-3 -(2-oxo-1Nimide azol-3-yl)- 6,7d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5(oxan-4-yl)in ol-1 -yl] 2-methylcyclopropyl] -4H1,2,4-oxadiazol-5 -He SMD-FA05-1 1.21 707 ([M+H] ⁺ )

- 38 044109

31- 40 (Connection 311) F N-Ν I/AL n Chg d'dd Ά A 3-[(lS,2S)-l-[5-[(4S)-2,2d imethyloxan-4-yl]-2[(48)-2-(4-fluoro-3,5dimethylphenyl)-4-methyl3 -(2-oxo-1H-imidazol-3yl)-6,7-dihydro-4Hpyrazolo[4,3-c]pyridin5-carbonyl]indol-1-yl]2-methylcyclopropyl]-4H1,2,4- oxadiazol-5-one SMD-FA05-1 1.29 735 ([M+H] ⁺ ) 41 (Connection 4 If) 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3,5-d imethylphenyl)4-methyl-3 -(2-oxo-1 Ifimid azol-3-yl) -6,7d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5[(2S, 48)-2-methyloxan-4yl]indol-1-yl]-2- methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SQD-FA05-1 0.96 722 ([M+H] ⁺ ) 42- 43 (42g connection) th“ Α.Λ- xbd A 3-[(lS,2S)-l-[2-[(4S)-2-(4chloro-3,5-d imethylphenyl)4-methyl-3 -(2-oxo-1 Ifimid azol-3 -yl) -6,7d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5[(4 8)-2,2-dimethyloxan-4yl]indol-1-yl]-2methylcyclopropyl]-4H1,2 ,4-oxadiazol-5-one SMD-FA05-1 1.34 751 ([M+H] ⁺ ) 44- 45 (Compound 44a) d 3-[(lS,2S)-l-[2-[(4S)-2-(4chloro-3,5-d imethylphenyl)4-methyl-3 -(2-oxo-1Nimide azol-3-yl)- 6.7- d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5(oxan-4-yl)in ol-1 -yl] 2-methylcyclopropyl] -4H1,2,4-oxadiazol-5-one SMD-FA05-1 1.27 723 ([M+H] ⁺ ) 46- 47 (Compound 46f) d Ν -N II ЛΑΛη Ν-φΑ)—(QA A 7 ^{H sL} o 3-[(lS,2S)-l-[2-[(4S)-2-(4fluoro-3-methylphenyl)-4methyl-3 -(2-oxo-1 Ifimid azol-3-yl)-6.7 - d ihydro-4H-pyrazolo[4,3 c]pyridin-5-carbonyl]-5(oxan-4-yl)in ol-1 -yl] 2-methylcyclopropyl] -4ff1,2, 4-oxadiazol-5-one SMD-FA05-1 1.16 693 ([M+H] ⁺ ) 48- 50 (Compound 48a) Η λ _Z A'N ' ^JH .. ο ΑΆ , L· ° ^L o 3-[(lS,2S)-l-[5-[(4S)-2,2d imethyloxan-4-yl]-2[(48)-2-(4-fluoro-3methylphenyl)-4-methyl-3 (2-oxo-1H-imide azol-3yl)-6,7-dihydro-4Hpyrazolo[4,3-c]pyridin5-carbonyl]indol-1-yl]2-methylcyclopropyl]4ff-1,2,4 -oxadiazol-5-one SMD-FA05-1 1.24 721 ([M+H] ⁺ )

- 39 044109

Table 2-3

Used halogenated compounds

Example No. Halogen containing compound Example No. Halogen containing compound Example No. Halogen containing compound 2 12 15 50 3 18 jxX 4 1 T 5 ώ 6 13 jOX ⁿ 7 I 16 31 \ O-. with 8 Xjx Br^^ 9 CD ъ. 04 o/ 10 F XX/ 14 22 C.Q. 17 O—i ω 19 HE 20 OH J. O Br^ ⁵⁵ ^ 21 from ъ Oh o' 23 41 50 I XjQ F 24 /=/ About ^Br 25 n^n Ji XX g Br X-^\ 1 26 F Γ £> Br^

- 40 044109

2-Oximidazole compound, (3-[(1S,2S)-1-[5-(2-ethyl-3-methylpyridin-4-yl)-2-[2-(4-fluoro-3,5dimethylphenyl)-3 -(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol1-yl]-2-methylcyclopropyl]-4H-1 ,2,4-oxadiazol-5-one, compound 2g), which was used in the synthesis of compounds of examples 2-5, was prepared by the following method.

Chemical formula 19

Stage 2-1.

4-Fluoro-3,5-dimethylaniline hydrochloride (compound 2b).

4-Fluoro-3,5-dimethylaniline (compound 2a, 3.97 g, 28.5 mmol) was added with stirring at room temperature, and a mixture of concentrated hydrochloric acid (20 ml) and water (20 ml) was stirred. The reaction mixture was stirred for 1 hour, at which temperature the solid from the reaction mixture was filtered and dried. To the resulting solid was added

- 41 044109 methoxycyclopentane (20 ml) and the mixture was stirred at 50°C for 1 hour, then at room temperature for 1.5 hours. The precipitated solid was filtered and washed with methoxycyclopentane (12 ml). The resulting solid was dried under reduced pressure to obtain the title compound 2b (4.88 g, 97% yield) as an off-white solid. The compound was directly transferred to the next stage, stage 2-2.

Stage 2-2.

(4-Fluoro-3,5-dimethylphenyl)hydrazine hydrochloride (compound 2c).

To compound 2b (1.00 g, 5.69 mmol) obtained in step 2-1, was added concentrated hydrochloric acid (10 ml) and an aqueous solution (2.4 ml of water) sodium nitrite (511 mg, 7.40 mmol ) for 1 min with vigorous stirring at 0°C, then the mixture was stirred at 0°C for 30 min. An aqueous solution (2.4 mL of water) of tin(II) chloride (2.27 g, 12.0 mmol) was then added over 2 min. Next, water (7 ml) was added and the mixture was stirred at room temperature for 1 hour. The solid from the reaction mixture was filtered and washed with water (2 ml). It was then dried to give the title compound 2c (1.75 g, 77% yield, 48% content) as a gray solid.

LC/MS mass spectrometry: m/z 155 ([M+H]+).

LC/MS retention time: 0.54 min (analytical conditions: SMD-FA05-1).

Stage 2-3.

tert-Butyl-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5carboxylate (compound 2d).

The title compound was prepared from compound 1b obtained in step 1-1 and compound 2c obtained in step 2-2 by performing a step similar to step 1-2 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 361 ([M+H]+).

LC/MS retention time: 1.04 min (analytical conditions: SMD-FA05-3).

Stage 2-4.

tert-Butyl-3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethylphenyl)-6,7-dihydro-4Hpyrazolo[4,3-c]pyridine-5-carboxylate (compound 2e ).

The title compound was prepared from compound 2d obtained in Step 2-3 by performing a step similar to Step 1-3 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 492 ([M+H]+).

LC/MS retention time: 1.07 min (analytical conditions: SMD-FA05-3).

Stage 2-5.

3-[2-(4-Fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1Nimidazol-2-one hydrochloride (compound 2f) .

The title compound was prepared from compound 2e obtained in Step 2-4 by performing a step similar to Step 1-4 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 328 ([M+H]+).

LC/MS retention time: 0.61 min (analytical conditions: SMD-FA05-3).

Stage 2-6.

3-[(1S,2S)-1-[5-(2-ethyl-3-methylpyridin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2- oxo-1Nimidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]4H-1,2,4- Oxadiazol-5-one (compound 2g).

The title compound was prepared from Compound 2f obtained in Step 2-5 and Compound 1o obtained in Step 1-9 by performing a step similar to Step 1-10 of Example 1 using an appropriate reagent. 2-oxymidazole compound (3-[(1S,2S)-1[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6 ,7-dihydro-4H-pyrazolo[4,3-c]pyridin5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1 ,2,4-oxadiazol5-one, compound 6i), which was used in the synthesis of the compound of Example 6, was prepared by the following method.

- 42 044109

Chemical formula 20

Stage 6-1.

5-Bromo-1-(cyanomethyl)-N-methyl-N-phenylindole-2-carboxamide (compound 6c) The title compound was prepared from 5-bromo-1-(cyanomethyl)indole-2-carboxylic acid (compound 6a ) and N-methylaniline (compound 6b), by performing a step similar to steps 1-10 of example 1, using the appropriate reagent.

LC/MS mass spectrometry: m/z 368 ([M+H]+).

LC/MS retention time: 1.25 min (analytical conditions: SMD-FA05-3).

Stage 6-2.

5-Bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-N-methyl-N-phenylindole-2-carboxamide (compound 6d).

The title compound was prepared from compound 6c obtained in Step 6-1 by performing a step similar to Steps 1-6 of Example 1 using an appropriate reagent.

LC/MS retention time: 1.37 min (analytical conditions: SMD-FA05-1). ¹ H-NMR (400 MHz, DMSO-de) δ: 7.69 (1H, s), 7.65-7.25 (7H, m), 6.02 (1H, brs), 3.44 (3H , s), 3.31 (3H, d, J=9.5 Hz), 2.04-1.74 (3H, m).

Stage 6-3.

5-Bromo-N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-Nphenylindole-2-carboxamide (compound 6e).

The title compound was prepared from compound 6d obtained in Step 6-2 by performing a step similar to Steps 1-8 of Example 1 using the appropriate reagent.

LC/MS mass spectrometry: m/z 467 ([M+H]+).

LC/MS retention time: 1.33 min (analytical conditions: SMD-FA05-01).

Stage 6-4.

5-Bromo-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (compound 6f) .

A mixture of compound 6e (9.70 g, 20.8 mmol) obtained in step 6-3, potassium hydroxide (11.7 g, 208 mmol) and methoxyethanol (41.5 ml) was stirred at 100 °C for 4 h While cooling with ice, 6N hydrochloric acid (51.9 ml) was added and the suspension was stirred at room temperature for 30 minutes. The solid was filtered and washed with water (29.1 mL), then dried under reduced pressure to give the title compound 6f (7.42 g, 95% yield) as a light brown solid.

LC/MS mass spectrometry: m/z 376 ([M-H] ^- ).

LC/MS retention time: 1.10 min (analytical conditions: SMD-FA05-2).

Stage 6-5.

5-(2-methoxy-3-methylpyridin-4-yl)-1-[(18,28)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3yl)cyclopropyl] indole-2-carboxylic acid (compound 6 h).

From a suspension of compound 6f (3.00 g, 7.93 mmol) obtained in step 6-4, palladium(II) acetate (0.178 g, 0.793 mmol), dicyclohexyl(2',4',6'-triisopropyl-[ 1,1'-biphenyl]-2-yl)phosphane (0.756 g, 1.587 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi( 1,3,2-dioxaborolane) (3.02 g, 11.9 mmol) and potassium phosphate (10.1 g, 47.6 mmol) in DMSO (34.7 ml) were evacuated at room temperature under reduced pressure, the vessel was then filled with nitrogen. Under a nitrogen atmosphere, the suspension was stirred at 100°C for 0.5 h, then cooled to room temperature. 4-iodo-2-methoxy-3methylpyridine (compound 6g, 1.98 g, 7.93 mmol) and water (4.96 mL) were added to the solution, and the solution was deaerated under reduced pressure. Nitrogen was introduced into the vessel and the solution was stirred at 100°C for 0.5 hours. After cooling to room temperature, water (12.4 ml) and formic acid (6 ml) were added to the solution. After filtration, the filtrate was directly purified by reverse phase chromatography (acetonitrile/water, 0.1% formic acid) to give the title compound 6h (1.83 g, 55% yield).

LC/MS mass spectrometry: m/z 421 ([M+H]+).

LC/MS retention time: 1.10 min (analytical conditions: SMD-FA05-1).

Stage 6-6.

3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro -4Hpyrazolo[4,3-c]pyridin-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1-yl]-2methylcyclopropyl]-4H-1,2,4-oxadiazole -5-one (compound 6i).

The title compound was prepared from Compound 2f obtained in Step 2-5 and Compound 6h obtained in Step 6-5 by performing a step similar to Step 1-10 of Example 1 using an appropriate reagent. The halogen-containing compound (1-(5bromoindazol-1-yl)-2-methylpropan-2-ol, compound 6l) used in the synthesis of the compound of Example 6 was prepared by the following method.

Stage 6-7.

1-(5-bromoindazol-1-yl)-2-methylpropan-2-ol (compound 6k).

Chemical formula 21

j 6 1

5-bromoindazole (compound 6k, 150 mg, 0.761 mmol) and 2,2-dimethyloxirane (compound 6k, 274 mg, 3.81 mmol) were dissolved in 1-methylpyrrolidin-2-one (NMP) (1.52 ml), and potassium carbonate (526 mg, 3.81 mmol) was added. The solution was stirred in a microwave reactor at 180°C for 30 minutes. Water was added to the reaction mixture and then extracted with ethyl acetate. The organic layer was washed with water and the solvent was evaporated under reduced pressure. The resulting product was purified by silica gel column chromatography (ethyl acetate/hexane=1:1) to give the title compound 61 (115 mg, 56% yield).

LC/MS mass spectrometry: m/z 269 ([M+H]+).

LC/MS retention time: 1.00 min (analytical conditions: SMD-FA05-2). Reagent containing 2-oxoimidazole (3-[(1S,2S)-1-[5-(2,2-dimethylmorpholin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3 -(2-oxoSH-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2methylcyclopropyl]-4H-1,2 ,4-oxadiazol-5-one, compound 7c), which was used in the synthesis of the compound of Example 7, was prepared by the following method.

- 44 044109

Chemical formula 22

Stage 7-1.

5-(2,2-dimethylmorpholin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3yl)cyclopropyl]indol- 2-carboxylic acid (compound 7b).

From a suspension of 2,2-dimethylmorpholine (compound 7a, 1.98 g, 17.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.121 g, 0.132 mmol), 2-dicyclohexylphosphino-2',6'diisopropoxy-1 ,1'-biphenyl (0.123 g, 0.264 mmol) and sodium t-butoxide (5.08 g, 529 mmol) in NMP (44 ml) were removed from air at room temperature under reduced pressure, then the vessel was filled with nitrogen. Under a nitrogen atmosphere, compound 6f (5.0 g, 13.2 mmol) obtained in step 6-4 was added to the suspension, and the mixture was stirred at 100° C. for 0.5 h, then cooled to room temperature. Formic acid was added to the mixture and the resulting product was directly purified by reverse phase chromatography (acetonitrile/water, 0.1% formic acid) to give the title compound 7b (5.26 g, 96% yield).

LC/MS mass spectrometry: m/z 413 ([M+H]+).

LC/MS retention time: 1.00 min (analytical conditions: SMD-FA05-1).

Stage 7-2.

3-[(1S,2S)-1-[5-(2,2-dimethylmorpholin-4-yl)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo- 1Himidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]4H-1,2,4-oxadiazol- 5-on (compound 7c).

The title compound was prepared from 7b obtained in Step 7-1 by performing a step similar to Steps 1-10 of Example 1 using the appropriate reagent.

Reagent containing 2-oxoimidazole (3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1Himidazol-3-yl)-6 ,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2methylcyclopropyl]-4H-1,2,4-oxadiazole -5-one, compound 8c) used in the synthesis of exemplary compounds 8-10 was prepared by the following method.

Chemical formula 23

Stage 8-1.

1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-(oxan-4-yl)indole-2carboxylic acid (compound 8b).

From a suspension of compound 6f (0.30 g, 0.793 mmol) obtained in step 6-4, palladium(II) acetate (35.6 mg, 0.159 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (0.148 g , 0.317 mmol) in N,N-dimethylacetamide (DMA) (2.64 ml) was removed under reduced pressure, then the vessel was filled with nitrogen and the suspension was stirred at room temperature for 15 minutes. Under nitrogen atmosphere, 1M (tetrahydro-2H-pyran-4-yl)zinc(II) iodide (compound 8a) in DMA (7.9 mL, 7.93 mmol) was added and the mixture was stirred at 80°C for 15 min. , and then the mixture was cooled to room temperature. Formic acid was added to the mixture and the resulting product was purified directly by reverse phase chromatography (methanol/water) to give the title compound 8b (0.19 g, 61% yield). LC/MS mass spectrometry: m/z 382 ([M-H] ^- ).

LC/MS retention time: 1.00 min (analytical conditions: SMD-FA05-2).

- 45 044109

Stage 8-2.

3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro -4Hpyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4oxadiazol-5-one (compound 8c).

The title compound was prepared from compound 8b obtained in Step 8-1 by performing a step similar to Steps 1-10 of Example 1 using the appropriate starting material.

The halogen-containing compound (5-bromo-1-[(3R)-oxolan-3-yl]indazole, compound 8f) used in the synthesis of the compound of Example 8 was prepared by the following method.

Chemical formula 24

Stage 8-3.

4-methylbenzenesulfonic acid [(3S)-oxolan-3-yl] (compound 8e).

To a solution of (3S)-oxolan-3-ol (compound 8d, 500 mg, 5.68 mmol) in dichloromethane (3.78 ml) was added pyridine (1.28 ml, 15.9 mmol) and 4-methylbenzenesulfonyl chloride (1 .51 g, 7.95 mmol) at 0°C. The solution was stirred at room temperature, then, after 15 hours, water and 1 N were added. hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The solvent was evaporated under reduced pressure to give the title compound 8e (1.36 g, 99% yield).

LC/MS retention time: 0.96 min (analytical conditions: SMD-FA05-1).

1H-NMR (400 MHz, CDCl3) δ: 7.79 (2H, d, J=8 Hz), 7.35 (2H, d, J=8 Hz), 5.12 (1H, m), 3, 93-3.76 (4H, m), 2.46 (3H, s), 2.13-2.05 (2H, m).

Stage 8-4.

5-Bromo-1-[(3R)-oxolan-3-yl]indazole (compound 8f).

To a solution of 5-bromo-1H-indazole (compound 6j, 300 mg, 1.52 mmol) in DMF (3.8 ml) was added cesium carbonate (992 mg, 3.05 mmol) and compound 8e (369 mg, 1. 52 mmol) obtained in step 8-3, and the mixture was stirred at 100°C for 2 hours. After cooling to room temperature, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and the solvent was evaporated under reduced pressure. The resulting product was purified by silica gel column chromatography (ethyl acetate/hexane=1:1) to give the title compound 8f (198 mg, 49% yield) as a colorless oil.

LC/MS mass spectrometry: m/z 267 ([M+H] ⁺ ).

LC/MS retention time: 1.07 min (analytical conditions: SMD-FA05-1). The halogen-containing compound (N-(4-bromo-2-methoxyphenyl)-N-(3-methoxypropyl) acetamide, compound 9c) used in the synthesis of the compound of Example 9 was prepared by the following method.

Stage 9-1.

Chemical formula 25

Sodium hydride (50 wt.%, oil dispersion) was successively added to a solution (0.8 ml) of N-(4-bromo-2-methoxyphenyl) acetamide (compound 9a, 80 mg, 0.33 mmol) in DMF (18, 9 mg 0.39 mmol)

1-Bromo-3-methoxypropane (75 mg, 0.49 mmol), and the resulting mixture was stirred at room temperature for 12 hours. Formic acid was added to the reaction solution and the resulting product was purified by reverse phase chromatography on silica gel (acetonitrile/water, 0. 1% formic acid) to obtain the title compound 9c (103 mg, 99% yield) as a colorless gummy product.

LC/MS mass spectrometry: m/z 316 ([M+H]+).

LC/MS retention time: 1.02 min (analytical conditions: SMD-FA05-1). Halogenated

- 46 044109 The compound (5-bromo-1-(2,2,2-trifluoroethyl)indazole, compound 10b) used in the synthesis of the compound of Example 10 was prepared by the following method.

Stage 10-1.

Chemical formula 26

The title compound was prepared starting from 2,2,2-trifluoroethyltrifluoromethanesulfonate (compound 10a) and 5-bromo-1H-indazole (compound 6j) by performing a step similar to step 8-4 of example 8 using the appropriate reagent.

LC/MS mass spectrometry: m/z 279 ([M+H]+).

LC/MS retention time: 1.17 min (analytical conditions: SMD-FA05-1). The starting 2oxoimidazole substance (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1Nimidazole- 3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4yl)indol-1-yl]-2- methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 11m) used in the synthesis of compounds of examples 11-13 was prepared by the following method.

Chemical formula 27

Stage 11-1.

tert-Butyl-N-(4-fluoro-3,5-dimethylphenyl)-N-[(2-methylpronan-2-yl)oxycarbonylamino]carbamate (compound 11b).

5-Bromo-2-fluoro-1,3-dimethylbenzene (compound 11a, 4.66 g, 22.6 mmol) was dissolved in THF (47.6 ml) and cooled at -70°C external temperature. 1.55 M n-butyllithium (13.1 mL, 20.4 mmol) was added dropwise at -70°C or below and stirred for 1 hour. A solution of 20 wt.%, di-tert-47 044109 butyl azodicarboxylate ( 25.0 g, 21.7 mmol) in toluene was added dropwise at an internal temperature of -40°C or lower, and the mixture was stirred for 30 minutes. The mixture was then warmed to room temperature for 1 hour and heptane (23.8 ml) and 20% ammonium chloride solution (47.6 ml) were added to perform extraction. The organic layer was evaporated and heptane (7.14 ml) was added to the concentrated organic layer and the mixture was heated to an external temperature of 70°C to promote dissolution. The solution was then cooled for 1 hour to cause crystal precipitation. The crystals were collected by filtration and washed with heptane (2.38 ml). The crystals were dried to give the crude product (3.53 g, 44% yield) of the title compound 11b.

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.64-9.51 (0.8H, m), 9.24-9.07 (0.2H, m), 7.09-6, 91 (2H, m), 2.29-2.09 (6H, m), 1.53-1.32 (18H, m).

LC/MS retention time: 1.40 min (analytical conditions: SMD-FA05-3).

Stages 11-2, 3 and 4.

tert-Butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid (compound 11g).

(3S)-3-Aminobutanenitrile hydrochloride (compound 11c, 10.0 g, 82.9 mmol) was dissolved in ethanol (50.0 mL) and triethylamine (13.9 mL, 99.5 mmol) and ethyl acrylate ( 10.8 ml, 99.5 mmol) at room temperature. The solution was stirred at an external temperature of 70°C for 3 hours, then cooled to room temperature to obtain a mixture containing ethyl 3-[[(2S)-1-cyanopropan-2yl]amino]propanoate (compound 11e).

Di-tert-butyl dicarbonate (21.7 mL, 99.5 mmol) was added to the reaction solution at room temperature. The solution was stirred at room temperature for 14 hours, then Nmethylpiperazine (2.76 ml, 24.9 mmol) was added and the mixture was stirred for 4 hours. Then 1N was added. hydrochloric acid (50 ml) and extracted using toluene (50 ml). The organic layer was washed with 15% aqueous sodium chloride solution (50.0 ml). The organic layer was evaporated under reduced pressure to obtain a mixture containing ethyl 3-[[(2S)-1-cyanopropan-2-yl]-[(2-methylpropan2-yl)oxycarbonyl]amino]propanoate (compound 11f). THF (50.0 mL) was added to the mixture, and then potassium tert-butoxide (10.2 g, 91.2 mmol) was added at an internal temperature of 30° C. or lower. The mixture was then stirred at room temperature for 1 hour. At an internal temperature of 15°C, 2N was added. hydrochloric acid (82.9 ml, 99.5 mmol) and extracted using ethyl acetate. The organic layer was evaporated after being washed twice with 15% sodium chloride aqueous solution (50.0 mL) to obtain the title compound 11g (15.8 g, 80% yield).

LC/MS mass spectrometry: m/z 237 ([M-H] ^- ).

LC/MS retention time: 0.92 min (analytical conditions: SMD-FA05-1).

Stage 11-5.

tert-Butyl (4S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3c]pyridine-5-carboxylate (compound 11h).

Compound 11b (2.13 g, 6.01 mmol) obtained in step 11-1 was dissolved in NMP (6.39 ml), methanesulfonic acid (1.30 g, 13.2 mmol) was added and the mixture was stirred at ambient temperature 80°C for 7 hours. After cooling the reaction solution to room temperature, toluene (12.8 ml), potassium carbonate (0.914 g) and water (12.8 g) were added thereto, and the reaction solution was stirred at room temperature for 10 min. After removing the aqueous layer, a toluene (6.3 ml) solution of compound 11g (1.43 g, 6.01 mmol) obtained in step 11-4 was added, pyridine hydrochloride (71.0 mg, 0.60 mmol) and toluene were added (4.2 ml), and the reaction solution was stirred at an external temperature of 90°C for 1 hour. The reaction solution was cooled, then washed with 1M sodium hydroxide aqueous solution (12.6 ml). The organic layer was evaporated under reduced pressure to give the title compound 11h (1.68 g, 75% yield).

LC/MS mass spectrometry: m/z 375 ([M+H]+).

LC/MS retention time: 1.08 min (analytical conditions: SMD-FA05-1).

Stage 11-6.

tert-Butyl (4S)-3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7dihydro-4H-pyrazolo[4,3-c]pyridine -5-carboxylate (compound 11j).

To a solution of compound 11h in DMA (0.53 ml) obtained in step 11-5 (106 mg, 0.283 mmol) was added N-(2,2-dimethoxyethyl)imidazole-1-carboxamide (compound 11i, 62.0 mg , 0.311 mol), then potassium tert-butoxide (95.0 mg, 0.849 mol) was added under nitrogen atmosphere and the mixture was stirred at an external temperature of 25°C for 4 hours. Water was added to the reaction solution and extraction was performed using ethyl acetate. The organic layer was washed with water and the solvent was evaporated under reduced pressure. The resulting product was purified by silica gel column chromatography (ethyl acetate/hexane=3:2) to give the title compound 11j (105 mg, 73% yield).

LC/MS mass spectrometry: m/z 506 ([M+H]+).

LC/MS retention time: 1.09 min (analytical conditions: SMD-FA05-1).

Stage 11-7.

tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro4H-pyrazolo[4 ,3-c]pyridine-5-carboxylate (compound 11k).

- 48 044109

Compound 11j (4.45 g, 8.79 mmol) obtained in step 11-6 was suspended by adding THF (44.5 ml), then methylsulfonic acid (0.676 g, 7.03 mmol) was added and the resulting mixture was stirred at external temperature 60°C for 2 hours. After cooling to room temperature, a solution of potassium orthophosphate (1.87 g, 8.79 mmol) in water (17.8 ml) was added, di-tert-butyl dicarbonate (0.768 g, 3.52 mmol) and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and extraction was carried out using ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried using magnesium sulfate. After filtration, the organic layer was evaporated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/hexane=3:7) to obtain the title compound 11k (3.43 g, 88% yield).

LC/MS mass spectrometry: m/z 442 ([M+H]+).

LC/MS retention time: 1.09 min (analytical conditions: SMD-FA05-1).

Stage 11-8.

3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydronirasolo[4,3c]pyridin-3-yl]-1H-imidazole hydrochloride -2-one (compound 11l).

To a solution of compound 11k (1.85 g, 4.19 mmol) in dichloromethane (8.38 mL) obtained in step 11-7 was added a 4 M solution of hydrochloric acid in dioxane (10.5 mL, 41.9 mmol). The mixture was stirred at room temperature for 1 hour and the reaction mixture was evaporated under reduced pressure to obtain a crude product (1.63 g) containing the title compound 11l as a brown solid.

LC/MS mass spectrometry: m/z 342 ([M+H]+).

LC/MS retention time: 0.63 min (analytical conditions: SMD-FA05-1).

Stage 11-9.

3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3- yl)-6,7dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(2-methoxy-3-methylpyridin-4-yl)indol-1 -yl]-2methylcyclopropyl]-4H -1,2,4-oxadiazol-5-one (compound 11m).

The title compound was prepared from Compound 11l obtained in Step 11-8 and Compound 6h obtained in Step 6-5 by performing a step similar to Steps 1-10 of Example 1 using the corresponding starting material.

The starting 2-oxoimidazole substance (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4methyl-3-(2-oxo-1H- imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(3-fluoro-2methylpyridin-4-yl)indol-1-yl]- 2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 14d) used in the synthesis of the compound of Example 14 was prepared by the following method.

Chemical formula 28

Stage 14-1.

5-(2-chloro-3-fluoropyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3yl)cyclopropyl] indole-2-carboxylic acid (compound 14b).

The title compound was prepared from compound 6f obtained in step 6-4 and 2-chloro-3-fluoro-4-iodopyridine (compound 14a) by performing a step similar to step 65 of example 6 using the appropriate starting material.

LC/MS mass spectrometry: m/z 429 ([M+H]+).

LC/MS retention time: 1.14 min (analytical conditions: SMD-TFA05-3).

Stage 14-2.

5-(3-fluoro-2-methylpyridin-4-yl)-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3yl)cyclopropyl] indole-2-carboxylic acid (compound 14c).

- 49 044109

From a 7:1 DMSO/water mixed suspension (13.2 mL) containing 14b (810 mg, 1.32 mmol) obtained in Step 14-1, 1,G-bis(diphenylphosphino)ferrocenepalladium(II) dichloride ( 48 mg, 0.066 mmol), potassium carbonate (2.74 g, 19.8 mmol), methyl boronic acid (792 mg, 13.2 mmol) were removed from air under reduced pressure and room temperature, then the vessel was filled with nitrogen. Under a nitrogen atmosphere, the mixture was stirred at 100°C for 0.5 h, then cooled to room temperature. Formic acid was added to the mixture, which was directly purified by reverse phase chromatography (acetonitrile/water, 0.1% formic acid) to give the title compound 14c (124 mg, 23% yield) as a pale yellow solid.

LC/MS mass spectrometry: m/z 409 ([M+H]+).

LC/MS retention time: 0.85 min (analytical conditions: SMD-FA05-3).

Stage 14-3.

3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3- yl)-6,7dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(3-fluoro-2-methylpyridin-4-yl)indol-1 -yl]-2methylcyclopropyl]-4H -1,2,4-oxadiazol-5-one (compound 14d).

The title compound was prepared from Compound 111 obtained in Step 11-8 and Compound 14c obtained in Step 14-2 by performing a step similar to Steps 1-10 of Example 1 using the corresponding starting material.

The starting 2-oxoimidazole substance (3-[(1S,2S)-1-[5-[2-(dimethylamino)-3-methylpyridin-4-yl]2-[(4S)-2-(4-fluoro-3 ,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4Hpyrazolo[4,3-c]pyridine-5-carbonyl]indole-1- yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 15d) used in the synthesis of the compound of Example 15 was prepared by the following method.

Chemical formula 29

Stage 15-1.

4-iodo-N,N,3-trimethylpyridin-2-amine (compound 15b).

A solution of 2-chloro-4-iodo-3-methylpyridine (compound 15a, 500 mg, 1.97 mmol), N-ethyl-N-propan-2ylpropan-2-amine (0.515 ml, 2.96 mmol) in DMF ( 7.9 ml) and a solution of 2M dimethylamine in THF (2.96 ml, 5.92 mmol) were stirred at 130°C for 17 hours, then the solution was cooled to room temperature and formic acid (0.4 ml) was added. The solution was purified by reverse phase chromatography (acetonitrile/water, 0.1% formic acid) to give the title compound 15b (258 mg, 50% yield) as a light brown solution.

LC/MS mass spectrometry: m/z 263 ([M+H]+).

LC/MS retention time: 0.52 min (analytical conditions: SQD-FA05-1).

Stage 15-2.

- [2-(dimethylamino)-3-methylpyridin-4-yl]-1-[(1 S,2S)-2-methyl-1 -(5-oxo-4H-1,2,4-oxadiazol-3 yl )cyclopropyl]indole-2-carboxylic acid (compound 15c).

The title compound was prepared from compound 6f obtained in step 6-4 and compound 15b obtained in step 15-1 by performing a step similar to step 6-5 of example 6 using the corresponding starting material.

LC/MS mass spectrometry: m/z 432 ([M-H] ^- ).

LC/MS retention time: 0.51 min (analytical conditions: SQD-FA05-1).

Stage 15-3.

3-[(1S,2S)-1-[5-[2-(dimethylamino)-3-methylpyridin-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -4methyl-3 -(2-oxo-1 H-imidazol-3 -yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5 -carbonyl]indol-1 -yl]-2methylcyclopropyl ]-4H-1,2,4-oxadiazol-5-one (compound 15d).

The title compound was prepared from compound 15c obtained in step 152 and compound 11l obtained in step 11-8 by performing a step similar to step 110 of Example 1 using the corresponding starting material.

The starting 2-oxoimidazole substance (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4methyl-3 -(2-oxo-1H -imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4yl)indol-1-yl]-2-methylcyclopropyl]- 4H-1,2,4-oxadiazol-5-one, compound 16a), used for

- 50 044109 synthesis of compounds of examples 16-30, was obtained by the following method.

Chemical formula 30

Stage 16-1.

3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3- yl)-6,7dihydro-4H-pyrazolo [4,3-c]pyridin-5-carbonyl] -5-(oxan-4-yl)indol-1 -yl] -2-methylcyclopropyl] -4H1,2,4 -oxadiazol-5-one (compound 16a).

The title compound was prepared from Compound 11l obtained in Step 11-8 and Compound 8b obtained in Step 8-1 by performing a step similar to Steps 1-10 of Example 1 using the corresponding starting material.

The halogen-containing compound (5-bromo-1-[(3-methyloxetan-3-yl)methyl]indazole, compound 17b) used in the synthesis of the compound of Example 17 was prepared by the following method.

Stage 17-1.

Chemical formula 31

The title compound was prepared starting from 3-methyl-3-[(4methylphenyl)sulfonylmethyl]oxetane (compound 17a) and 5-bromo-1H-indazole (compound 6j) by performing a step similar to step 9-1 of example 9 using the corresponding starting substance.

LC/MS mass spectrometry: m/z 281 ([M+H]+).

LC/MS retention time: 1.10 min (analytical conditions: SMD-FA05-2). The halogen-containing compound (2-(4-bromo-2-methoxyphenoxy)-2-methylpropan-1-ol, compound 20b) used in the synthesis of the compound of Example 20 was prepared by the following method.

Stage 20-1.

2-(4-bromo-2-methoxyphenoxy)-2-methylpropan-1-ol (compound 20b).

Chemical formula 32

20b

20a

Under a nitrogen atmosphere, THF solution (0.95 M, 4.37 mL, 4.15 mmol) of borane was added dropwise at 0°C to a THF solution (1.38 mL) of 2-(4-bromo-2-methoxyphenoxy)- 2-methylpropanecarboxylic acid (compound 20a, 400 mg, 1.38 mmol) and the resulting mixture was stirred for 24 hours. After adding 1 M aqueous sodium hydroxide solution to the mixture and stirring the mixture, 1N was added. hydrochloric acid for neutralization. Ethyl acetate was then added to perform extraction. The organic layer was washed with water and the solvent was removed by evaporation under reduced pressure to give the title compound 20b (339 mg, 89% yield).

LC/MS retention time: 1.04 min (analytical conditions: SMD-FA05-3).

1H-NMR (400 MHz, CDCl ₃ ) δ: 7.04-7.01 (2H, m), 6.90-6.86 (1H, m), 3.85 (3H, s), 3.44 (2H, m), 3.34 (1H, m) 1.28 (6H, s).

The halogen-containing compound (5-bromo-1-[(3S)-oxolan-3-yl]indazole, compound 22c) used in the synthesis of the compound of Example 22 was prepared by the following method.

- 51 044109

Chemical formula 33 n

Stage 22-1.

(3R)-oxolan-3-yl 4-methylbenzenesulfonate (compound 22b).

The title compound was synthesized by a similar step to Step 8-3 of Example 8 using (3R)-oxolan-3-ol and the appropriate starting material.

LC/MS retention time: 0.95 min (analytical conditions: SMD-FA05-3).

Stage 22-2.

5-Bromo-1-[(3S)-oxolan-3-yl]indazole (compound 22c).

The title compound was synthesized from compound 22b obtained in step 22-1 and 5-bromo-1H-indazole by performing a step similar to step 8-4 of example 8 using the appropriate starting material.

LC/MS mass spectrometry: m/z 267 ([M+H]+).

LC/MS retention time: 1.06 min (analytical conditions: SMD-FA05-3). The halogen-containing compound (6-bromo-1,1-dimethyl-3,4-dihydroisochromene, compound 24d) used in the synthesis of the compound of Example 24 was prepared by the following method.

Chemical formula 34

Stage 24-1.

(1,1-dimethyl-3,4-dihydroisochromen-6-yl)trifluoromethanesulfonate (compound 24b).

The title compound was prepared from 1,1-dimethyl-3,4-dihydroisochromen-6-ol (compound 24a) and trifluoromethylsulfonyl trifluoromethanesulfonate (triflate anhydride) by a similar step to step 8-3 of example 8 using the appropriate starting material substances.

LC/MS retention time: 0.96 min (analytical conditions: SQD-FA05-01).

Stage 24-2.

2-(1,1-dimethyl-3,4-dihydroisochromen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound 24c).

After 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (147 mg, 0.580 mmol), triethylamine (0.162 ml, 1.16 mmol), [1,1'-bis(diphenylphosphino))ferrocene]dichloropalladium ( II) (14.2 mg, 0.019 mmol) in 1,4-dioxane (2.58 ml) was removed from air under reduced pressure, the vessel was purged with nitrogen and the solution was stirred at 100°C for 14 hours. The solution was cooled to room temperature then formic acid was added and the resulting product was purified by reverse phase chromatography (acetonitrile/water, 0.1% formic acid) to give a mixture (134 mg) containing the title compound 24c as a light brown solution.

LC/MS mass spectrometry: m/z 289 ([M+H] ⁺ ).

LC/MS retention time: 1.03 min (analytical conditions: SQD-FA05-1).

Stage 24-3.

6-Bromo-1,1-dimethyl-3,4-dihydroisochromene (compound 24d).

To the methanol (1.9 ml) solution of compound 24c (111 mg, 0.385 mmol) obtained in step 24-2, was added an aqueous solution (1.9 ml) of copper(II) bromide (258 mg, 1.16 mmol) and the mixture was stirred at 60°C for 6 hours. After cooling the mixture to room temperature, a saturated ammonium chloride solution was added, then extracted twice with dichloromethane, and then the organic layer was dried over magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:4) to obtain the title compound 24d (47.7 mg, 51% yield) as a colorless liquid.

- 52 044109

1H-NMR (400 MHz, CDCl3) δ: 7.29 (1H, dd, J=2.0, 8.4 Hz), 7.24-7.22 (1H, m), 6.97 (1H, d, J=8.4 Hz),

3.92 (2H, t, J=5.6 Hz), 2.80 (2H, t, J=5.6 Hz), 1.50 (6H, s).

LC/MS retention time: 0.96 min (analytical conditions: SQD-FA05-1). The halogen-containing compound (6-(4-bromo-2-methylphenyl)-N,N-dimethylpyrimidin-4-amine, compound 25b) used in the synthesis of the compound of Example 25 was prepared by the following method.

Chemical formula 35

Stage 25-1.

6-(4-Bromo-2-methylphenyl)-N,N-dimethylpyrimidin-4-amine (compound 25b).

To a methanol (0.2 ml) solution of 4-(4-bromo-2-methylphenyl)-6-chloropyrimidine (compound 25a, 12.9 mg, 0.045 mmol) was added a 2M solution of dimethylamine in THF (0.227 ml, 0.455 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by reverse phase chromatography on silica gel (acetonitrile/water, 0.1% formic acid) to give the title compound 25b (9.2 mg, 69% yield) as white solid.

LC/MS mass spectrometry: m/z 292 ([M+H]+).

LC/MS retention time: 0.67 min (analytical conditions: SMD-FA05-3). The halogen-containing compound (5-bromo-4-fluoro-1-(2,2,2-trifluoroethyl)indazole, compound 28b) used in the synthesis of the compound of Example 28 was prepared by the following method.

Chemical formula 36

Stage 28-1.

5-Bromo-4-fluoro-1-(2,2,2-trifluoroethyl)indazole (compound 28b).

The title compound was prepared starting from 2,2,2-trifluoroethyltrifluoromethanesulfonate (compound 10a) and 5-bromo-4-fluoro-1H-indazole (compound 28a) by performing a step similar to step 8-4 of example 8 using the appropriate original substance.

LC/MS mass spectrometry: m/z 297 ([M+H]+).

LC/MS retention time: 1.20 min (analytical conditions: SMD-FA05-1). The halogen-containing compound (5-bromo-4-fluoro-1-[(3-methyloxetan-3-yl)methyl]indazole, compound 29a) used in the synthesis of the compound of Example 29 was prepared by the following method.

Chemical formula 37

Stage 29-1.

5-Bromo-4-fluoro-1-[(3-methyloxetan-3-yl)methyl]indazole (compound 29a).

The title compound was prepared from 3-methyl-3-[(4methylphenyl)sulfonylmethyl]oxetane (compound 17a) and 5-bromo-4-fluoro-1H-indazole (compound 28a) by a step similar to step 8-4 example 8 using the appropriate starting material.

LC/MS mass spectrometry: m/z 299 ([M+H]+).

LC/MS retention time: 1.11 min (analytical conditions: SMD-FA05-1). The halogen-containing compound (1-(5-bromo-4-fluorinazol-1-yl)-2-methylpropan-2-ol, compound 30a) used in the synthesis of the compound of Example 30 was prepared by the following method.

- 53 044109

Chemical formula 38

Stage 30-1.

-(5-bromo-4-fluorinazol-1-yl)-2-methylpropan-2-ol (compound 30a).

The title compound was prepared starting from 5-bromo-4-fluoro-1H-indazole (compound 28a) and 2,2-dimethyloxirane (compound 6k) by performing a step similar to step 6-7 of example 6 using the appropriate starting material .

LC/MS mass spectrometry: m/z 287 ([M+H]+).

LC/MS retention time: 1.01 min (analytical conditions: SMD-FA05-1). 2oxoimidazole reagent (3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5 -dimethylphenyl)-4methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl ]-2methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 311), used in the synthesis of compounds of examples 31-40, was prepared by the following method.

Chemical formula 39

Stage 31-1.

Ethyl 5-(2,2-dimethyloxan-4-yl)-1H-indole-2-carboxylate (compound 31c).

Zinc powder (1.95 g, 29.8 mmol) was suspended in DMF (6 ml) and nitrogen was purged through the suspension. Chlorotrimethylsilane (0.417 mL, 3.28 mmol) and 1,2-dibromoethane (0.284 mL, 3.28 mmol) were added and the resulting mixture was stirred at room temperature for 5 min. A solution of 4-iodo-2,2-dimethyltetrahydropyran (5.37 g, 22.4 mmol) in DMF (9 mL) was added dropwise to the mixture, and the mixture was stirred at room temperature for 20 minutes. To this solution were added palladium(II) acetate (0.084 g, 0.373 mmol) and 4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (0.198 g, 0.746 mol), ethyl 5-bromoindole-2-carboxylate ( 2.0 g, 7.46 mmol) and the vessel was purged with nitrogen. The mixture was stirred

- 54 044109 at an external temperature of 50°C for 1 hour, then the external temperature was lowered to 0°C and 5N was added for neutralization. hydrochloric acid (6 ml). 30% aqueous sodium chloride (50 ml) and ethyl acetate (100 ml) were added and undissolved substances were removed with cerite. The filtrate was extracted using ethyl acetate and the organic layer was washed with 30% sodium chloride aqueous solution. It was then dried with magnesium sulfate and passed through a filter, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound 31c (1.86 g, 83% yield) as a pale pink solid.

LC/MS mass spectrometry: m/z 302 ([M+H]+).

LC/MS retention time: 0.90 min (analytical conditions: SQD-FA05-4).

Stage 31-2.

Ethyl 5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indole-2-carboxylate (compound 31d).

Stereoisomers included in compound 31c (900 mg) obtained in step 31-1 were separated by supercritical fluid chromatography to obtain the title compound 31d (423 mg, 47% yield).

Conditions of separation.

Tool: SFC15 (Waters).

Column: CHIRALPAK-IE/SFC, 10x250 mm, 5 µm (Daicel).

Column temperature: 40°C.

Solvent: supercritical carbon dioxide/methanol:ethyl acetate (1:1)=60/40 (homogeneous system).

Flow rate: 15 ml/min, 140 bar Analytical conditions.

Tool: Nexera (Shimadzu).

Column: CHIRALPAK-IE, 4.6x250 mm, 5 µm (Daicel).

Column temperature: 25°C.

Solvent: hexane/ethanol=30/70 (homogeneous system).

Flow rate: 1 ml/min, room temperature.

Title compound retention time: 9.98 min, isomer retention time: 6.86 min.

It should be noted that the title compound was identified as the S-isomer by X-ray crystallography of compound 31j.

Stage 31-3.

5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indole-2-carboxylic acid (compound 31e).

Compound 31d (993 mg, 3.29 mmol) obtained in step 31-2 was dissolved in methanol (14.9 ml), and 2M aqueous sodium hydroxide solution (3.62 ml, 7.25 mmol) was added dropwise to the mixture. ) and the mixture was stirred at an external temperature of 65°C for 1 hour. The reaction solution was cooled at an external temperature of 15°C, and 5N was added dropwise to the reaction solution. hydrochloric acid (1.52 ml, 7.58 mmol). Water (7.45 ml) was added dropwise and the precipitated solid was collected by filtration. The resulting solid was washed with water (5.0 mL) and dried under reduced pressure to give the title compound 31e (827 mg, 96% yield).

LC/MS mass spectrometry: m/z 274 ([M+H]+).

LC/MS retention time: 0.65 min (analytical conditions: SQD-FA05-4).

Stage 31-4.

5-[(4S)-2,2-dimethyloxan-4-yl]-N-methyl-N-phenyl-1H-indole-2-carboxamide (compound 31f).

Compound 31e (805 mg, 2.95 mmol) obtained in step 31-3 was dissolved in DMA (8.0 ml) and thionyl chloride (0.256 ml, 3.53 mmol) was added dropwise to the solution at an internal temperature of 10 °C. or lower. After stirring the solution for an hour, N-methylaniline (0.384 mL, 3.53 mmol) and triethylamine (0.985 mL, 7.07 mmol) were added dropwise at 10 °C or lower, and the solution was stirred at room temperature for 1 h. Water (4.0 ml) was added dropwise to the solution, and the precipitated solid was collected by filtration. The resulting solid was washed with water (8.0 mL) and dried under reduced pressure to give the title compound 31f (995 mg, 93% yield).

LC/MS mass spectrometry: m/z 363 ([M+H]+).

LC/MS retention time: 1.20 min (analytical conditions: SMD-FA05-1).

Stage 31-5.

1-(Cyanomethyl)-5-[(4S)-2,2-dimethyloxan-4-yl]-N-methyl-N-phenylindole-2-carboxamide (compound 31h).

Compound 31f (101 mg, 0.276 mmol) obtained in step 31-4 was dissolved in 1,3-dimethyl-2imidazolidinone (DMI) (1.0 ml) at room temperature and 8 M aqueous potassium hydroxide (0.103 ml) was added to the solution , 0.828 mmol) and water (0.10 ml). 2chloroacetonitrile (0.026 ml, 0.414 mmol) was added to the resulting solution at an external temperature of 10°C and the solution was stirred until

- 55 044109 reading 2.5 hours 5n. hydrochloric acid (0.193 ml), water (0.10 ml) and cyclopentyl methyl ether (1.0 ml) were added to the reaction solution to perform extraction, and the aqueous layer was subjected to a second extraction using cyclopentyl methyl ether (1.0 ml). The combined organic layer was washed with 15% sodium chloride solution (1.0 ml), then the title compound 31h was obtained as a light brown oil by evaporation under reduced pressure at an external temperature of 40°C and used in the next step 31-6 without cleaning.

LC/MS mass spectrometry: m/z 402 ([M+H]+).

LC/MS retention time: 0.93 min (analytical conditions: SMD-FA05-1).

Stage 31-6.

1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-5-[(4S)-2,2-dimethyloxan-4-yl]-N-methyl-N-phenylindole-2carboxylate (compound 31i).

The title compound was prepared from compound 31h obtained in Step 31-5 by performing a step similar to Steps 1-6 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 442 ([M+H]+).

LC/MS retention time: 0.95 min (analytical conditions: SQD-FA05-1).

Stage 31-7.

5-[(4S)-2,2-dimethyloxan-4-yl]-N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4- Oxadiazol-3yl)cyclopropyl]-X-phenylindole-2-carboxamide (compound 31j).

The title compound was prepared from compound 31i obtained in Step 31-6 by performing a similar step to Steps 1-6 of Example 1 using the appropriate starting material.

LC/MS mass spectrometry: m/z 501 ([M+H]+).

LC/MS retention time: 0.99 min (analytical conditions: SQD-FA05-1).

Stage 31-8.

5-[(4S)-2,2-dimethyloxan-4-yl]-1-[(1 S,2S)-2-methyl-1 -(5-oxo-4H-1,2,4-oxadiazol-3 yl)cyclopropyl]indole-2-carboxylic acid (compound 31k).

The title compound was prepared from compound 31j obtained in Step 31-7 by performing a step similar to Step 6-4 of Example 6 using the appropriate starting material.

LC/MS mass spectrometry: m/z 401 ([M-H]-).

LC/MS retention time: 1.05 min (analytical conditions: SMD-FA05-1).

Stage 31-9.

3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -4-methyl-3-(2oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one (compound 311).

The title compound was prepared from Compound 11l obtained in Step 11-8 and Compound 31k obtained in Step 31-8 by performing a step similar to Steps 1-10 of Example 1 using the corresponding starting material.

The halogen-containing compound 5-bromo-1-(2-methoxyethyl)-3-methylbenzoimidazol-2-one (compound 33b) used in the synthesis of the compound of Example 33 was prepared by the following method.

Stage 33-1.

Chemical formula 40

The title compound was prepared starting from 5-bromo-3-methyl-1H-benzoimidazol-2-one (compound 33a) by performing a step similar to step 8-4 of example 8 using the appropriate starting material.

LC/MS mass spectrometry: m/z 285 ([M+H]+).

LC/MS retention time: 0.95 min (analytical conditions: SMD-FA05-1). The halogen-containing compound (5-bromo-4-fluoro-1-(2-methoxyethyl)indazole, compound 36a) used in the synthesis of the compound of Example 36 was prepared by the following method.

Stage 36-1.

- 56 044109

Chemical formula 41

The title compound was prepared from 5-bromo-4-fluoro-1H-indazole (compound 28a) by performing a step similar to step 8-4 of example 8 using the appropriate starting material. LC/MS mass spectrometry: m/z 273 ([M+H]+).

LC/MS retention time: 1.10 min (analytical conditions: SMD-FA05-1). The halogen-containing compound (5-bromo-4-fluoro-1-[(3S)-oxolan-3-yl]indazole, compound 40a) used in the synthesis of the compound of Example 40 was prepared by the following method.

Stage 40-1.

Chemical formula 42

The title compound was prepared from 5-bromo-4-fluoro-1H-indazole (compound 28a) and (3R)-oxolan-3-yl-4-methylbenzenesulfonate (compound 22b) by performing a similar step to Example 8-4 8 using the appropriate starting material.

LC/MS mass spectrometry: m/z 285 ([M+H]+).

LC/MS retention time: 1.10 min (analytical conditions: SMD-FA05-1). Reagent containing 2-oxoimidazole (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo- 1H-imidazol-3yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-[(2S,4S)-2-methyloxan-4-yl]indol-1 -yl]-2methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 41f) used in the synthesis of the compound of Example 41 was prepared by the following method.

Chemical formula 43

Stages 41-1 and 2.

1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-N-methyl-5-[(2S,4S)-2-methyloxαn-4-yl]-N-phenylindole-2carboxamide (compound 41c).

After removing air from the DMA (0.12 mL) zinc suspension (29 mg, 0.44 mmol) at room temperature, the vessel was filled with nitrogen. Under a nitrogen atmosphere, a 7:5 mixed solution of chlorotrimethylsilane/1,2-dibromoethane (0.0083 mL, 0.039 mmol chlorotrimethylsilane) was added and the mixture was stirred for 15 min, then (2S)-4-iodo-2-methyltetrahydro-2H-pyran (80 mg, 0.35 mmol) was added dropwise at room temperature and the mixture was stirred for 30 min to obtain a mixture containing iodo-[(2S)2-methyloxan-4-yl]zinc (compound 41b). Palladium(II) acetate (6.4 mg, 0.028 mmol), 2dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (26 mg, 0.057 mmol), 5-bromo-1-[(1S,2S)-1-cyano- 2methylcyclopropyl]-N-methyl-N-phenylindole-2-carboxamide (58 mg, 0.14 mmol) and DMA (0.123 ml), and from

- 57 044109 air was removed from the mixture under reduced pressure, then the vessel was filled with nitrogen and the mixture was stirred for an hour at 80°C. The mixture was cooled to room temperature, to which ethyl acetate and 1N were added. hydrochloric acid and the mixture was filtered. The filtrate was then extracted using ethyl acetate. The organic layer was washed once with saturated aqueous sodium chloride and evaporated under reduced pressure, then the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:1) to give the title compound 41c (31 mg, 51% yield).

LC/MS mass spectrometry: m/z 428 ([M+H]+).

LC/MS retention time: 1.01 min (analytical conditions: SQD-AA05-1).

Stage 41-3.

N-methyl-5-[(2S,4S)-2-methyloxan-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4- Oxadiazol-3yl)cyclopropyl]-N-phenylindole-2-carboxamide (compound 41d).

The title compound was prepared from compound 41c obtained in step 41-2 by performing a step similar to steps 1-8 of Example 1 using the appropriate starting material.

LC/MS mass spectrometry: m/z 487 ([M+H]+).

LC/MS retention time: 1.30 min (analytical conditions: SMD-FA05-1).

Stage 41-4.

5-[(2S,4S)-2-methyloxan-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3yl) cyclopropyl]indole-2-carboxylic acid (compound 41e).

The title compound was prepared from compound 41d obtained in step 41-3 by performing a step similar to step 6-4 of example 6 using the appropriate starting material.

LC/MS mass spectrometry: m/z 396 ([M-H] ^- ).

LC/MS retention time: 1.02 min (analytical conditions: SMD-FA05-1).

Stage 41-5.

3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3- yl)-6,7dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-[(2S,4S)-2-methyloxan-4-yl]indol-1-yl]-2methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one (compound 41f).

The title compound was prepared from Compound 41e obtained in Step 41-4 by performing a step similar to Steps 1-10 of Example 1 using the appropriate starting material.

2-oxoimidazole reagent (3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1Himidazole -3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4yl]indol-1-yl] -2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 42g) used in the synthesis of Examples 42 and 43 was prepared by the following method.

Chemical formula 44

Stages 42-1.2.

tert-Butyl (4S)-3-amino-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3c]pyridine-5-carboxylate (compound 42c).

After (4-chloro-3,5-dimethylphenyl)hydrazine hydrochloride (compound 42b) was prepared from 4-chloro-3,5-dimethylaniline (compound 42a) by performing a step similar to step 2-2 of example 2 using corresponding starting material, compound 11g, obtained from

- 58 044109 step 11-4, and the corresponding reagent was used to synthesize compound 42c using an operation similar to step 1-2 of example 1.

LC/MS mass spectrometry: m/z 391 ([M+H]+).

LC/MS retention time: 1.22 min (analytical conditions: SMD-FA10-4).

Stage 42-3.

tert-Butyl (4S)-2-(4-chloro-3,5-dimethylphenyl)-3-(2,2-dimethoxyethylcarbamoylamino)-4-methyl-6,7dihydro-4H-pyrazolo[4,3-c]pyridine -5-carboxylate (compound 42d).

The title compound was prepared from compound 42c obtained in step 42-2 by performing a step similar to steps 1-3 of Example 1 using the appropriate reagent.

LC/MS mass spectrometry: m/z 522 ([M+H]+).

LC/MS retention time: 1.55 min (analytical conditions: SMD-TFA05-5).

Stage 42-4.

tert-Butyl (4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro4H-pyrazolo[4 ,3-c]pyridine-5-carboxylate (compound 42e).

The title compound was prepared from compound 42d obtained in step 42-3 by performing a step similar to step 11-8 of example 11 using the appropriate reagent.

LC/MS mass spectrometry: m/z 458 ([M+H]+).

LC/MS retention time: 1.16 min (analytical conditions: SMD-FA05-1).

Stage 42-5.

3-[(48)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3c]pyridin-3-yl]-1H-imidazole hydrochloride -2-ona (compound 42f).

The title compound was prepared from compound 42e obtained in step 42-4 by performing a step similar to step 111-8 of example 11 using the appropriate starting material.

LC/MS mass spectrometry: m/z 358 ([M+H]+).

LC/MS retention time: 0.69 min (analytical conditions: SMD-FA05-1).

Stage 42-6.

3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3- yl)-6,7dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]indol-1 -yl]-2methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one (compound 42 g).

The title compound was prepared from compound 42f obtained in step 42-5 and compound 31k obtained in step 31-8 by performing a step similar to steps 1-10 of example 1 using the appropriate reagent. The reagent containing the compound 2oxoimidazole (3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H -imidazol-3-yl)6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl] 4H-1,2,4-oxadiazol-5-one, compound 44a), used in the synthesis of compounds of example 44 and 45 were synthesized by the following method.

Chemical formula 45

Stage 44-1.

3-[(1S,2S)-1-[2-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3- yl)-6,7dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H1,2,4 -oxadiazol-5-one (compound 44a).

The title compound was prepared from compound 42f obtained in step 42-5 and compound 8b obtained in step 8-1 by performing a step similar to step 1-10 of example 1 using the corresponding starting material.

Reagent containing 2-oxoimidazole, (3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2)oxo- Sh-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4-yl)indol-1yl]-2-methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one, compound 46f), used in the synthesis of examples 46 and 47, was prepared as follows.

Chemical formula 46

Stage 46-1.

tert-Butyl (4S)-3-amino-2-(4-fluoro-3-methylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3c]pyridine-5-carboxylate (compound 46b) .

The title compound was prepared from (4-fluoro-3-methylphenyl)hydrazine hydrochloride (compound 46a) and compound 11g obtained in Step 11-4 by performing a step similar to Steps 1-2 of Example 1 using the appropriate reagent.

LC/MS mass spectrometry: m/z 361 ([M+H]+).

LC/MS retention time: 1.02 min (analytical conditions: SMD-FA05-1).

Stage 46-2.

tert-Butyl (4S)-3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3-methylphenyl)-4-methyl-6,7dihydro-4H-pyrazolo[4,3-c]pyridine-5 -carboxylate (compound 46c).

The title compound was prepared from compound 46b obtained in Step 46-1 by performing a step similar to Steps 1-3 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 492 ([M+H]+).

LC/MS retention time: 1.03 min (analytical conditions: SMD-FA05-1).

Stage 46-3.

tert-Butyl (4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4Hpyrazolo[4,3 -c]pyridine-5-carboxylate (compound 46d).

The title compound was prepared from compound 46c obtained in step 46-2 by performing a step similar to step 11-7 of example 11 using the appropriate reagent.

LC/MS mass spectrometry: m/z 428 ([M+H]+).

LC/MS retention time: 2.11 min (analytical conditions: SMD-FA05-long).

Stage 46-4.

3-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin3-yl]-1H-imidazole hydrochloride -2 -on (compound 46e).

The title compound was prepared from compound 46d obtained in step 46-3 by performing a step similar to step 11-8 of example 11 using the appropriate starting material.

LC/MS mass spectrometry: m/z 328 ([M+H]+).

LC/MS retention time: 0.59 min (analytical conditions: SMD-FA05-3).

Stage 46-5.

3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-3-(2-oxo-1H-imudazol-3-yl) -6,7-dihydro4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4oxadiazole -5-one (compound 46f).

The title compound was prepared from compound 46e obtained in step 46-4 and compound 8b obtained in step 8-1 by performing a step similar to steps 1-10 of example 1 using the appropriate reagent.

- 60 044109

A reagent containing 2-oxoimidazole, (3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4fluoro- 3-methylphenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5carbonyl]indol-1-yl ]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, compound 48a), which was used for the synthesis of compounds of examples 48-50, was prepared by the following method.

Chemical formula 47

Stage 48-1.

3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3-methylphenyl)-4 -methyl-3-(2-oxo1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2methylcyclopropyl]-4H -1,2,4-oxadiazol-5-one (compound 48a).

The title compound was prepared from compound 46e obtained in step 46-5 and compound 31k obtained in step 31-8 by performing a step similar to steps 1-10 of Example 1 using the appropriate reagent.

Examples 51-53.

A step similar to step 7-1 of Example 7 was carried out using 3-[(1S,2S)-1-[5-5poM-2-[2(4-fluoro-3,5-dimethylphenyl)-3-[3- (1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4Hpyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2-methylcyclopropyl] -4H-1,2,4-oxadiazol-5-one (compound 51d), substituted morpholine and the corresponding reagent to prepare exemplary compounds 51-53, illustrated in table. 2-4, using the following reaction.

Chemical formula 48

- 61 044109

Table 2-4

Resultant compounds of Examples 51-53

Example No. Structure Compound Analytical conditions LC/MS retention time (min.) LC/MS mass spectrometer IA (m/z) 51 A A / 3-[(lS,2S)-l-[2-[2-(4fluoro-3,5- dimethylphenyl)-3 [3 -(1-methylindazol5-yl)-2oxoimidazol-1 yl]-6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl]-5-(5oxa-8- azaspiro[3,5]nonan8-yl)indol-1 -yl]-2methylcyclopropyl]4H-1D4oxadiazol-5-one SMDTFA05-3 1.31 864 ([M+H] ⁺ ) 52 3-[(lS,2S)-l-[2-[2-(4- fluorine-3.5- d methylphenyl)-3 [3 -(1-methylindazol5-yl)-2oxoimidazol-1yl]-6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl]-5-(4oxa-7- azaspiro[2,5]octan7-yl)indol-1-yl]-2methylcyclopropyl]4H-1,2,4oxadiazol-5-one SMDTFA05-3 1.16 850 ([M+H] ⁺ ) 53 a I. 3-[(lS,2S)-l-[5- [(2S)-2- ethylmorpholin-4yl]-2-[2-(4-fluoro-3,5d and methylphenyl)-3 [3 -(1 -methylindazol- 5-yl)-2- oxoimidazol-1 -yl]6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl]indole-1 - ill]-2- methylcyclopropyl]4H-1,2,4oxadiazol-5-one SMDTFA05-3 1.21 852 ([M+H] ⁺ )

- 62 044109

Compound 51d was prepared as follows.

Chemical formula 49

Stage 51-1.

tert-Butyl-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4Hpyrazolo[4,3-c]pyridin- 5-carboxylate (compound 51a).

To a suspension of dichloromethane (16.8 ml) of compound 2f (0.611 g, 1.68 mmol) obtained in step 2-5 was added triethylamine (0.936 ml, 6.72 mmol), di-tert-butyl dicarbonate (0.425 ml, 1 .85 mmol) and the suspension was stirred at room temperature for 2 hours. Water (20.0 ml) and 5% aqueous potassium hydrogen sulfate (20.0 ml) were added to the reaction solution, then extracted with dichloromethane and the resulting product was dried with using magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0:1 to 1:0) to obtain the title compound 51a (0.360 g, 50% yield).

LC/MS mass spectrometry: m/z 428 ([M+H]+).

LC/MS retention time: 1.06 min (analytical conditions: SMD-FA05-3).

Stage 51-2.

tert-Butyl-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7dihydro-4H-pyrazolo[ 4,3-c]pyridine-5-carboxylate (compound 51b).

The title compound was prepared from Compound 51a obtained in Step 51-1 and 5-bromo-1-methylindazole by a similar step to Steps 1-11 of Example 1 using the appropriate starting material.

LC/MS mass spectrometry: m/z 558 ([M+H]+).

LC/MS retention time: 1.25 min (analytical conditions: SMD-FA05-1).

Stage 51-3.

1-[2-(4-Fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1methylindazol-5-yl) hydrochloride imidazol-2-one (compound 51c).

The title compound was prepared from compound 51b obtained in Step 51-2 by performing a step similar to Step 11-9 of Example 11 using the appropriate reagent.

LC/MS mass spectrometry: m/z 458 ([M+H]+).

LC/MS retention time: 0.78 min (analytical conditions: SMD-FA05-1).

Stage 51-4.

3-[(1S,2S)-1-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4oxadiazol-5-one (connection 51d).

The title compound was prepared from compound 51c obtained in step 51-3 and compound 6f obtained in step 6-4 by performing a step similar to step 1-10 of example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 817 ([M+H]+).

LC/MS retention time: 1.41 min (analytical conditions: SMD-FA05-1).

Examples 54-73.

A step similar to Step 1-10 of Example 1 was carried out using an amine derivative and a carboxylic acid derivative to prepare the compounds of Examples 54-72 illustrated in

- 63 044109 table 2-5, and the compounds of example 73 using the following reaction.

Chemical formula 50

Table 2-5

Resultant compounds of Examples 54-72

Example No. Structure Compound Analytical conditions Retention time lc/m s (min.) LC/MS mass spectrometry (m/z) 54 G 3-[(lS,2S)-l-[2-[2-(4fluoro-3,5- dimethylphenyl)-3-[3(1-methylindazol-5yl)-2-oxoimidazol-1yl]-6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl]-5-(oxan-4yl)indol- 1 -yl]-2methylcyclopropyl]- 4H-1, 2,4-oxadiazol5-one SMD- TFA05-3 1.41 823 55 X, V 'L/ 3-[(lS,2S)-l-[2-[2-(4chloro-3,5dimethylphenyl)-3-[3(1-methylindazol-5 yl)-2-oxoimidazol-1 yl]-6,7- Dihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl]-5-(oxan-4yl)indol-1 -yl]-2methylcyclopropyl]4H-1, 2,4-oxadiazol5-one SMD- TFA05-2 1.43 839

- 64 044109

56 A 3-[(lS,2S)-l-[2-[2-(4- fluorine-3.5- dimethylphenyl)-3- [3[1-(2methoxyethyl)indazol5-yl]-2 - oxoimidazol-1 -yl] 6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl]-5-(oxan-4yl) pyrrolo[2,3- b]pyridin 1-yl]-2methylcyclopropyl]4H-1,2,4-oxadiazol5-one SMDTFA05-2 1.23 868 57 XA CHCL l U-. pj /L/ > । ^z N-[4-[3-[(4S)-2-(4fluoro-3,5dimethylphenyl)-4methyl-5-[l-[(lS,2S)-2methyl-1 -(5-oxo-4H1,2, 4-oxadiazol-3-yl) cyclopropyl]-5(oxan-4-yl)indol-2carbonyl]-6,7dihydro-4Hpyrazolo[4,3 - c]pyr idin-3 -yl]-2oxoimid azol-1 -yl] ku ban-1 -yl] -N-(2methoxyethyl)acetamide SMD- TFA05-1 1.34 924 58 ь А >ч<XJyC 0 Y \=< Г| ^/ ^Л / I,. / ShchN '4 3-[(lS, 2S)-l-[5-(2,2dimethylmorpholin-4yl)-2-[2-(4-fluoro-3 methyl phenyl)-3 - [3 - [ 1 2- methoxyethyl)indazol5-yl]-2-oxoimidazol1-yl]-6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl]indol-1yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol5-one SMDTFA05-3 1.29 883

- 65 044109

59 ^ci A 3-[(lS,2S)-l-[5-[(4S)2,2-dimethyloxan-4yl]-2-[2-(4-fluoro-3,5 dimethylphenyl)-3-[3(1 - methylindazol-5 yl)-2-oxoimidazol-1 yl]-6,7-d ihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl]indol-1yl]- 2- methylcyclopropyl] 4H-1,2,4-oxadiazol5-one SMDTFA05-2 1.44 851 60 A%d .d ⁿ 3-[(lS,2S)-l-[5-[(4S)- 2,2-dimethyloxan-4yl]-2-[2-(3,5dimethylphenyl)-3 -[3 - (1-methylindazol-5yl)-2-oxoimidazol-1yl]-6,7-d ihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl]indol-1yl]-2methylcyclopropyl]4H-1,2,4-oxadiazol5- He SMDTFA05-1 1.41 833 61 9 0\ 3-[(lS,2S)-l-[2-[(4S)- 2-(4-fluoro-3,5dimethylphenyl)-4methyl-3-[3-(1- methylindazol-5 -yl)-2oxoimid azol-1 -yl] 6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5- carbonyl]-5-[(28,4S)2-methyloxan-4-yl] indol-1-yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol5-one SMDTFA05-1 1.45 851 62 ° δ, i 3-[(lS,2S)-l-[2-[(4S)- 2-(4-fluoro-3,5dimethylphenyl)-3 -[3 [1-(2- methoxyethyl)indazol5-yl]-2- oxoimid azol-1 -yl]-4methyl-6,7-dihydro4H-pyrazolo[4,3 c]pyridin-5- carbonyl]-5-[(28.48)- 2-methyloxane-4- yl] indol-1 -yl] -2methylcyclopropyl] 4H-1,2,4-oxadiazol5-one SMDTFA05-1 1.45 895

- 66 044109

63 Η-χ Λ\/V 3-[(18.28)-1-[7-fluoro2-[(48)-2-(4-fluoro-3,5- dimethylphenyl)-3 - [3 [1-(2- methoxyethyl)indazol5-yl]-2-oxoimidazol1 -yl]-4-methyl-6,7 dihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl]-5-(4-oxanyl)indol-1 -yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol5-one SMDTFA05-1 1.38 899 64 ⁼ 2 3-[(18.28)-1-[7-fluoro2-[(48)-2-(4-fluoro-3,5dimethylphenyl)-4methyl-3 -[2-oxo-3 - [ 1 [(3Y) -oxolan-3yl] indazol-5 -yl] imidazol-1 -yl]-6,7 dihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl]-5-(oxan-4yl)indol-1 -yl] -2methylcyclopropyl] 4H-1,2,4-oxadiazol5-one SMDTFA05-1 1.38 911 65 Όα. L >, \=/ 'X 3-[(lS,2S)-l-[2-[(4S)- 2-(4-chloro-3,5 dimethylphenyl)-3-[3(4-fluoro-1- methylindazol-5 -yl)-2oxoimid azol-1 -yl]-4methyl-6,7-dihydro4H-pyrazolo[4,3 c]pyridin-5carbonyl]-5-[(48)-2,2dimethyloxane -4- yl] indol-1 -yl] -2methylcyclopropyl] 4H-1,2,4-oxadiazol5-one SMDTFA05-1 1.53 899

- 67 044109

66 A. YOU M 3-[(lS,2S)-l-[5-[(4S)- 2,2-dimethyloxan-4yl]-2-[(4 8)-2-(4-fluoro3,5-dimethylphenyl)-4methyl-3-[3-(1- methylindazol-5 -yl)-2oxoimid azol-1 -yl] 6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl] indole-1- yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol5-one SMDTFA05-2 1.47 866 67 LL X.AJQ ^N L)La G L Sl 3-[(lS,2S)-l-[5-[(4S)- 2,2-dimethyloxan-4yl]-2-[(4 8)-2-(4-fluoro- 3,5-dimethylphenyl)-3 [3-(4-fluoro-1methylindazol-5 -yl)-2oxoimid azol-1 -yl]-4methyl-6,7-dihydro4H-pyrazolo[4,3 c]pyridine -5- carbonyl]indol-1yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol5-one SMDTFA05-1 1.46 883 68 U- njjjy '%Υ. % ^Ν -X 3-[(lS,2S)-l-[2-[(4S)3- [3-(4-chloro-1- methylindazol-5 -yl)-2oxoimid azol-1 -yl]-2(4-fluoro-3,5dimethylphenyl)-4methyl-6,7-dihydro4H-pyrazolo[4,3 c]pyridin-5carbonyl]-5-[( 48)-2,2dimethyloxane -4- yl] indol-1 -yl] -2methylcyclopropyl] 4H-1,2,4-oxadiazol5-one SMDTFA05-1 1.47 899

- 68 044109

69 gzh 0 3-[(lS,2S)-l-[5-[(4S)- 2,2-dimethyloxan-4yl]-2-[(48)-3-[3-(4- fluoro-1-methylind azol -5-yl)-2- oxoimid azol-1-yl]-2(4-fluoro-3- methylphenyl)-4-methyl6,7-dihydro-4Hpyrazolo[4,3- c]pyridine-5 - carbonyl]indol-1yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol5-one SMDTFA05-1 1.40 869 70 A\=/ Rg Chh, 3-[(lS,2S)-l-[5-[(4S)- 2,2-dimethyloxan-4yl]-2-[(4 8)-2-(4-fluoro- 3, 5-dimethylphenyl)-3 [3-(6-fluoro-1methylindazol-5 -yl)-2oxoimid azol-1 -yl]-4methyl-6,7-dihydro4H-pyrazolo[4,3 c]pyridine -5- carbonyl]indol-1yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol5-one SMDTFA05-1 1.43 883 71 and Ή·ή i 3-[(lS,2S)-l-[5-[(4S)- 2,2-dimethyloxan-4yl]-2-[(4 8)-2-(4-fluoro- 3, 5-dimethylphenyl)-3 [3-[6-fluoro-1-(2- methoxyethyl)indazol5-yl]-2-oxoimidazol1 -yl]-4-methyl-6,7 dihydro-4H- pyrazolo[4, 3- c]pyridin-5carbonyl]indol-1yl]-2methylcyclopropyl]4H-1,2,4-oxadiazol5-one SMDTFA05-1 1.44 927 72 Ή about 4.9 3-[(lS,2S)-l-[2-[(4S)3- [3-(4-chloro-1- methylindazol-5 -yl)-2oxoimid azol-1 -yl]-2(4-fluoro-3,5dimethylphenyl)-4methyl-6,7-dihydro4H-pyrazolo[4,3 c]pyridin-5carbonyl]-5-(oxane -4yl)indol-1yl]-2- methylcyclopropyl] 4H-1,2,4-oxadiazol5-one SMDTFA05-1 1.40 871

It should be noted that the compounds in the table. 2-5 have rotational isomers, and as an example, the ¹ H-NMR spectrum of examples 66 and 67 is shown below.

Compound Example 66.

Main rotamer.

Ή-NMR (600 MHz, CDCIs) δ: 11.32 (IH, s), 8.04 (IH, d, J=0.4 Hz), 7.86 (1H, d, J=1.4 Hz ), 7.61 (IH, m) 7.59 (IH, m), 7.52 (IH, s), 7.50 (H, d, J=9.0 Hz), 7.27 (1H, m), 7.15 (2H, d, Jhf=6.0 Hz), 6.74 (1H, d, J=3.1 Hz), 6.70 (1H, s), 6.32 (1H, d, J=3.1 Hz), 5.79 (1H, kv, J=6.6 Hz), 4.47 (1H, dd, J=13.6, 5.0 Hz), 4.12 ( 3H, s), 3.893.81 (2H, m), 3.60 (1H, ddd, J=13.6, 13.1, 3.6 Hz), 3.15 (1H, ddd, J=16, 0, 13.1, 5.0 Hz), 3.09-2.98 (2H, m), 2.27 (6H, d, J _hf =1.4 Hz), 1.91 (1H, dd, J=6.0 Hz), 1.82-1.60 (4H, m), 1.60-1.50 (2H, m), 1.55 (3H, d, J=6.6 Hz), 1.34 (3H, s), 1.28 (3H, s), 1.19 (3H, d, J=5.9 Hz).

- 69 044109

Second rotamer.

Ή-NMR (600 MHz, CDCI3) δ: 11.26 (1H, s), 7.93 (1H, s), 7.65 (1H, s), 7.57 (1H, d, J=8, 6 Hz), 7.49 (1H, m), 7.34 (2H, s), 7.25 (1H, m), 7.05 (2H, d, J _HF =6.0 Hz), 6, 69 (1H, s), 6.59 (1H, d, J=3.1 Hz), 6.09 (1H, d, J=3.1 Hz), 5.26 (1H, kv, J=6 ,6 Hz), 4.87 (1H, dd, J=12.8, 5.1 Hz), 4.07 (3H, s), 3.90-3.78 (2H, m), 3.40 (1H, ddd, J=12.8, 12.6, 4.5 Hz), 3.10-2.98 (3H, m), 2.23 (6H, s), 1.82-1.37 (10H, m), 1.33 (3H, s), 1.25 (3H, s), 1.06 (3H, d, J=6.2 Hz).

Compound of example 67.

Main rotamer.

1H-NMR (600 MHz, CDCl3) δ: 11.32 (1H, s), 8.13 (1H, d, Jhf=0.7 Hz), 7.59 (1H, d, J=8.6 Hz ), 7.52 (1H, s), 7.48 (1H, dd, J=8.9 Hz, Jhf=6.9 Hz), 7.28 (1H, d, J=8.9 Hz), 7.26 (1H, dd, J=8.6, 1.7 Hz), 7.16 (2H, d, Jhf=6.1 Hz), 6.70 (1H, s), 6.61 (1H , dd, J=3.0 Hz, Jhf=1.1 Hz), 6.31 (1H, d, J=3.0 Hz), 5.79 (1H, q, J=6.7 Hz), 4.47 (1H, dd, J=13.5, 5.2 Hz), 4.12 (3H, s), 3.88 (1H, m), 3.83 (1H, m), 3.60 (1H, ddd, J=13.5, 12.9, 3.6 Hz), 3.15 (1H, ddd, J=15.8, 12.9, 5.2 Hz), 3.04 (1H , m), 3.00 (1H, m), 2.29 (6H, d, Jhf=1.1 Hz), 1.91 (1H, dd, J=6.1, 5.8 Hz), 1 .79-1.76 (2H, m), 1.74 (1H, m), 1.65 (1H, m), 1.57 (3H, d, J=6.7 Hz), 1.60- 1.55 (1H, m), 1.52 (1H, dd, J=9.5, 5.8 Hz), 1.34 (3H, s), 1.28 (3H, s), 1.20 (3H, d, J=6.0 Hz).

Second rotamer.

Ή-NMR (600 MHz, CDCl ₃ ) δ: 11.27 (1H, s), 8.04 (1H, s), 7.55 (1H, d, J=8.7 Hz), 7.52 ( 1H, s), 7.25-7.22 (2H, m), 7.12 (1H, d, J=8.8 Hz), 7.06 (2H, d, Jhf=6.0 Hz), 6.71 (1H, s), 6.47 (1H, m), 6.08 (1H, d, J=3.0 Hz), 5.26 (1H, kv, J=6.6 Hz), 4.87 (1H, dd, J=13.l, 4.8 Hz), 4.07 (3H, s), 3.90-3.80 (2H, m), 3.39 (1H, ddd, J=13.l, 12.2, 4.6 Hz), 3.08-2.97 (3H, m), 2.25 (6H, s), 1.79-1.73 (3H, m) , 1.67 (3H, d, J=6.6 Hz), 1.64 (1H, m), 1.45-1.37 (2H, m), 1.34 (3H, s), 1, 28 (3H, s), 1.06 (3H, d, J=6.0 Hz).

Compound 55e used in the synthesis of Example Compound 55 was prepared as follows.

Chemical formula 51

Stage 55-1.

tert-Butyl-3-amino-2-(4-chloro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5 carboxylate (compound 55a).

The title compound was prepared from Compound 42a obtained in Step 42-1 and Compound 1b obtained in Step 1-1 by performing a step similar to Step 1-2 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 377 ([M+H]+).

LC/MS retention time: 0.87 min (analytical conditions: SQD-FA05-1).

Stage 55-2.

tert-Butyl-2-(4-chloro-3,5-dimethylphenyl)-3-(2,2-dimethoxyethylcarbamoylamino)-6,7-dihydro-4Hpyrazolo[4,3-c]pyridine-5-carboxylate (compound 55b ).

The title compound was prepared from compound 55a obtained in step 551 by performing a step similar to steps 1-3 of example 1 using the appropriate starting material.

LC/MS mass spectrometry: m/z 508 ([M+H]+).

LC/MS retention time: 0.83 min (analytical conditions: SQD-FA05-1).

Stage 55-3.

tert-Butyl-2-(4-chloro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4Hpyrazolo[4,3-c]pyridin- 5-carboxylate (compound 55c).

A suspension of compound 55b (903 mg, 1.78 mmol) in DMF (7.11 ml) obtained in step 55-2 and p-toluenesulfonic acid monohydrate (338 mg, 1.78 mmol) was stirred at 80°C for 1 hour. After the suspension was cooled to room temperature, potassium phosphate (377 mg, 1.78 mmol), water (3.5 ml) and di-tert-butyl dicarbonate (388 mg, 1.78 mmol) were added and the resulting mixture was stirred at

- 70 044109 room temperature for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate, then the organic layer was washed with a saturated aqueous sodium chloride solution and the resulting product was dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:4 to 1:0) to obtain the title compound 55c (799 mg, 100% yield) as a pale yellow foam. .

LC/MS mass spectrometry: m/z 444 ([M+H]+).

LC/MS retention time: 0.82 min (analytical conditions: SQD-FA05-1).

Stage 55-4.

tert-Butyl-2-(4-chloro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7dihydro-4H-pyrazolo [ 4,3-c]pyridine-5-carboxylate (compound 55d).

The title compound was prepared from compound 55 c obtained in step 553 and 5-bromo-1-methylindazole (compound 1q) by performing a step similar to step 1-11 of example 1 using the appropriate starting material.

LC/MS mass spectrometry: m/z 574 ([M+H]+).

LC/MS retention time: 1.34 min (analytical conditions: SMD-FA05-1).

Stage 55-5.

1-[2-(4-chloro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1methylindazol-5-yl) hydrochloride imidazol-2-one (compound 55e).

The title compound was prepared from compound 55d obtained in step 55-4 by performing a step similar to step 11-8 of example 11 using the appropriate reagent.

LC/MS mass spectrometry: m/z 474 ([M+H]+).

LC/MS retention time: 0.81 min (analytical conditions: SMD-FA05-1).

Compound 56c used in the synthesis of Example 56 was prepared as follows.

Chemical formula 52

Stage 56-1.

tert-Butyl-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1yl]-6,7-dihydro -4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 5 6b).

The title compound was prepared starting from compound 51a obtained in step 51-1 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) by performing a step similar to step 1-11 of example 1 using the corresponding starting material substances.

LC/MS mass spectrometry: m/z 602 ([M+H]+).

LC/MS retention time: 1.30 min (analytical conditions: SMD-FA05-2).

Stage 56-2.

1-2-(4-Fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1(2-methoxyethyl)indazole hydrochloride -5-yl]imidazol-2-one (compound 56c).

The title compound was prepared from compound 56b obtained in step 56-1 by performing a step similar to step 11-8 of example 11 using the appropriate starting material.

LC/MS mass spectrometry: m/z 502 ([M+H]+).

LC/MS retention time: 0.54 min (analytical conditions: SQD-FA05-1). The amine derivative (compound 57j) used in the synthesis of Example 57 was prepared as follows.

- 71 044109

Chemical formula 53

Stage 57-1.

tert-Butyl-N-(4-isocyanatocuban-1-yl)carbamate (compound 57b).

Triethylamine (0.0676 mL, 0.487 mmol) and diphenylphosphoryl azide (0.10 ml, 0.465 mmol), and the resulting mixture was stirred at room temperature for 100 minutes, then at 85°C for 3.5 hours. The solvent in the reaction mixture was evaporated under reduced pressure and indicated in The title compound 57b was obtained as the crude product.

Ή-NMR (400 MHz, CDCl ₃ ) δ: 12.3 (1H, br.s), 3.95 (6H, br. s), 1.45 (9H, s).

Stage 57-2.

tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[[4-[(2-methylpropan-2-yl)oxycarbonylamino]cuban-1-yl]carbamoylamino ]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 57c).

The title compound was prepared from compound 57b obtained in step 57-1 and compound 11h obtained in step 11-5 by performing a step similar to steps 1-3 of Example 1 using the corresponding starting material.

LC/MS mass spectrometry: m/z 636 ([M+H]+).

LC/MS retention time: 0.93 min (analytical conditions: SQD-FA05-1).

Stage 57-3.

tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[5-hydroxy-3-[4-[(2-methylpropan-2-yl)oxycarbonylamino]cuban-1-yl ]-2-oxoimidazolidin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3c]pyridine-5-carboxylate (compound 57d).

To a suspension of compound 57c (31.6 mg, 0.050 mmol) in DMA (0.25 ml) obtained in step 57-2 and cesium carbonate (82.8 mg, 0.254 mmol) was added 1,2-dichloro at room temperature -1-ethoxyethane (0.0155 ml, 0.127 mmol) and the mixture was stirred at room temperature for 170 minutes. Cesium carbonate (104 mg, 0.32 mmol) was added, and then 1,2-dichloro-1-ethoxyethane (0.0184 mL, 0.162 mmol) was added to the reaction mixture at room temperature, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and water, then 1N was added. hydrochloric acid (0.54 ml) to adjust the pH to 7, and then extracted using ethyl acetate. The organic layer was dried using magnesium sulfate, then the solvent was evaporated under reduced pressure, and then toluene was added and the solvent was evaporated under reduced pressure to obtain the title compound 57d as a crude product.

LC/MS mass spectrometry: m/z 678 ([M+H]+).

LC/MS retention time: 0.98 min (analytical conditions: SQD-FA05-1).

Stage 57-4.

tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-[4-[(2-methylpropan-2yl)oxycarbonylamino]cuban-1 -yl] - 2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5carboxylate (compound 57e).

To a solution of compound 57d (115 mg, 0.17 mmol) in THF (1.1 ml) obtained in step 57-3, methylsulfonic acid (0.011 ml, 0.17 mmol) was added at room temperature, then the mixture was stirred at 60 °C for 90 min. Potassium phosphate (36.5 mg, 0.172 mmol), water (0.45 mL), and (2-methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (0.012 mL, 0.052 mmol) were added to the reaction mixture, and the resulting mixture was stirred for 1 hour. Then, after the reaction mixture was diluted with dichloromethane, it was washed with water. The organic layer was dried using magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:2 to 1:1) to give the title compound 57e (48.5 mg, 43% yield).

LC/MS mass spectrometry: m/z 660 ([M+H]+).

LC/MS retention time: 1.04 min (analytical conditions: SQD-FA05-1).

Stage 57-5.

tert-Butyl (4S)-3-[3-[4-[acetyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]cuban-1-yl]-2oxoimidazol-1-yl]-2-(4 -fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5carboxylate (compound 57f).

To a solution of compound 57e (16.1 mg, 0.024 mmol) in THF (0.22 ml) obtained in step 57-4, 1.7 M toluene solution of potassium pentoxide (0.024 ml, 0.041 mmol) was added at -26°C. and the mixture was stirred at -30°C for 3 minutes. Acetic anhydride (8 μl, 0.085 mmol) was added to the reaction mixture at -30°C and the mixture was stirred at -30 to -25°C for 5 minutes, and at -25°C to room temperature for 3 min. After water (0.5 ml) was added to the reaction mixture, the mixture was diluted with ethyl acetate and additional water was added, and extracted with ethyl acetate. The organic layer was dried using magnesium sulfate, and the solvent was removed by distillation under reduced pressure, then the resulting product was purified by silica gel column chromatography (ethyl acetate/hexane=1:3 to 2:3) to obtain the title compound 57f (9.2 mg , yield 54%).

LC/MS mass spectrometry: m/z 701 ([M+H]+).

LC/MS retention time: 1.12 min (analytical conditions: SQD-FA05-1).

Stage 57-6.

N-[4-[3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3 ,2yl]-2-oxoimidazol-1-yl]cuban-1-yl]acetamide 2,2,2-trifluoroacetate (compound 57 g).

To a solution of compound 57F (8.5 mg, 0.012 mmol) in dichloromethane (0.097 ml) obtained in step 57-5, TFA (0.019 ml) was added at room temperature, and the resulting mixture was stirred at room temperature for 3 hours. After the solvent in the reaction mixture was removed by evaporation under reduced pressure, toluene was added and the solvent was evaporated, and hexanedichloromethane was added and the solvent was evaporated to obtain the title compound 57 g (9.4 mg) as crude product.

LC/MS mass spectrometry: m/z 501 ([M+H]+).

LC/MS retention time: 0.49 min (analytical conditions: SQD-FA05-1).

Stage 57-7.

tert-Butyl (4S)-3-[3-(4-acetamidecuban-1-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4methyl-6,7 -dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 57h).

The title compound was prepared from compound 57g obtained in Step 57-6 by performing a step similar to Step 51-1 of Example 51 using the appropriate starting material.

LC/MS mass spectrometry: m/z 602 ([M+H]+).

LC/MS retention time: 0.85 min (analytical conditions: SQD-FA05-1).

Stage 57-8.

tert-Butyl (4S)-3-[3-[4-[acetyl(2-methoxyethyl)amino]cuban-1-yl]-2-oxoimidazol-1-yl]-2-(4-fluoro3,5-dimethylphenyl )-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 57i).

The title compound was prepared from compound 57h obtained in Step 57-7 by performing a step similar to Step 57-5 of Example 57 using the appropriate starting material.

LC/MS mass spectrometry: m/z 660 ([M+H]+). LC/MS retention time: 0.93 min (analytical conditions: SQD-FA05-1).

- 73 044109

Stage 57-9.

N-[4-[3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3yl ]-2-oxoimidazol-1-yl]cuban-1-yl]A-(2-methoxyethyl)acetamide hydrochloride (compound 57j).

The title compound was prepared from compound 57i obtained in step 57-8 by performing a step similar to step 11-8 of example 11 using the appropriate starting material.

LC/MS mass spectrometry: m/z 560 ([M+H]+).

LC/MS retention time: 0.53 min (analytical conditions: SQD-FA05-1).

Compound 58E used in the synthesis of Example 58 was prepared as follows.

Chemical formula 54

Stage 58-1.

tert-Butyl-3-amino-2-(4-fluoro-3-methylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5carboxylate (compound 58a).

The title compound was prepared from Compound 1b obtained in Step 1-1 and Compound 46a obtained in Step 46-1 by performing a step similar to Step 1-2 of Example 1 using the corresponding starting material.

LC/MS mass spectrometry: m/z 347 ([M+H]+).

LC/MS retention time: 0.98 min (analytical conditions: SMD-FA05-3).

Stage 58-2.

tert-Butyl-3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3-methylphenyl)-6,7-dihydro-4Hpyrazolo[4,3-c]pyridine-5-carboxylate (compound 58b).

The title compound was prepared from compound 58a obtained in Step 58-1 by performing a step similar to Steps 1-3 of Example 1 using the appropriate starting material.

LC/MS mass spectrometry: m/z 478 ([M+H]+).

LC/MS retention time: 1.03 min (analytical conditions: SMD-FA05-3).

Stage 58-3.

tert-Butyl-2-(4-fluoro-3-methylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3c]pyridine 5-carboxylate (connection 58c).

The title compound was prepared from compound 58b obtained in step 58-2 by performing a step similar to step 11-7 of example 11 using the appropriate reagent.

LC/MS mass spectrometry: m/z 414 ([M+H]+).

LC/MS retention time: 0.72 min (analytical conditions: SQD-FA05-1).

Stage 58-4.

tert-Butyl-2-(4-fluoro-3-methylphenyl)-3-[3-[1-(2-methoxyethyl)indazol-5-yl]-2-oxoimidazol-1-yl]6,7-dihydro- 4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 58d).

The title compound was prepared starting from compound 58c obtained in step 58-3 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) by performing a step similar to steps 1-11 of example 1 using the corresponding starting material substances.

LC/MS mass spectrometry: m/z 588 ([M+H]+).

LC/MS retention time: 0.88 min (analytical conditions: SQD-FA05-1).

Stage 58-5.

1-[2-(4-Fluoro-3-methylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[1-(2methoxyethyl)indazole-5 hydrochloride -yl]imidazol-2-one (compound 58e).

- 74 044109

The title compound was prepared from compound 58d obtained in Step 58-4 by performing a step similar to Step 11-9 of Example 11 using the appropriate starting material.

LC/MS mass spectrometry: m/z 488 ([M+H]+). LC/MS retention time: 0.50 min (analytical conditions: SQD-FA05-1).

Compound 60c used in the synthesis of Example 60 was prepared by the following method.

Chemical formula 55

Stage 60-1.

tert-Butyl-2-(3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3c]pyridine-5-carboxylate ( connection 60a).

The title compound was prepared from Compound 1g obtained in Steps 1-4 by performing a step similar to Step 51-1 of Example 51 using the appropriate starting material.

LC/MS mass spectrometry: m/z 410 ([M+H]+).

LC/MS retention time: 0.77 min (analytical conditions: SQD-FA05-1).

Stage 60-2.

tert-Butyl-2-(3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro4H-pyrazolo[4,3- c]pyridine-5-carboxylate (compound 60b).

The title compound was prepared from compound 60a obtained in step 60-1 and 5-bromo-1-methylindazole (compound 1q) by performing a step similar to step 1-11 of example 1 using the corresponding starting material.

LC/MS mass spectrometry: m/z 540 ([M+H]+).

LC/MS retention time: 1.24 min (analytical conditions: SMD-FA05-3).

Stage 60-3.

1-[2-(3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-e]pyridin-3-yl]-3-(1methylindazol-5-yl)imidazol-2-hydrochloride she (connection 60s).

The title compound was prepared from compound 60b obtained in step 60-2 by performing a step similar to step 11-8 of example 11 using the appropriate reagent.

LC/MS mass spectrometry: m/z 440 ([M+H]+).

LC/MS retention time: 0.74 min (analytical conditions: SMD-FA05-2).

Compound 61b used in the synthesis of Example 61 was prepared using the following method.

Chemical formula 56

Stage 61-1.

tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol1 -yl]-6.7 -dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 61a).

The title compound was prepared from compound 11k obtained in step 11-7 and 5-bromo-1-methylindazole (compound 1q) by performing a step similar to steps 1-11 of Example 1 using the corresponding starting material.

LC/MS mass spectrometry: m/z 572 ([M+H]+).

LC/MS retention time: 1.30 min (analytical conditions: SMD-FA05-1).

Stage 61-2.

1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3c]pyridin-3-yl]-3 -( hydrochloride 1-methylindazol-5-yl)imidazol-2-one (compound 61b).

The title compound was prepared from compound 61a obtained in step 61-1 by performing a step similar to step 11-8 of example 11 using the appropriate reagent.

LC/MS mass spectrometry: m/z 472 ([M+H]+).

LC/MS retention time: 0.79 min (analytical conditions: SMD-FA05-1).

Compound 62b used in the synthesis of Example 62 was prepared using the following method.

Chemical formula 57 o

Stage 62-1.

tert-Butyl (48)-2-(4-fluoro-3,5-dimethylphenyl)-3 -[3-[1 -(2-methoxyethyl)indazol-5-yl]-2oxoimidazol-1-yl]-4- methyl 6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 62a).

The title compound was prepared starting from compound 11k obtained in step 11-7 and 5-bromo-1-(2-methoxyethyl)indazole (compound 56a) by performing a step similar to step 1-11 of example 1 using the corresponding starting material substances.

LC/MS mass spectrometry: m/z 616 ([M+H]+).

LC/MS retention time: 1.29 min (analytical conditions: SMD-FA05-1).

Stage 62-2.

1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3c]pyridin-3-yl]-3-[ hydrochloride 1-(2-methoxyethyl)indazol-5-yl]imidazol-2-one (compound 62b).

The title compound was prepared from compound 62a obtained in step 62-1 by performing a step similar to step 11-8 of example 11 using the appropriate reagent.

LC/MS mass spectrometry: m/z 516 ([M+H]+).

LC/MS retention time: 0.76 min (analytical conditions: SMD-FA05-1).

Compound 63 g used in the synthesis of Example 63 was prepared using the following method.

Chemical formula 58

Stage 63-1.

5-Bromo-7-fluoro-N-methyl-N-phenyl-1 H-indole-2-carboxamide (compound 63 b).

The title compound was prepared from 5-bromo-7-fluoro-1H-indole-2-carboxylic acid (compound 63 a) by performing a step similar to steps 1-10 of Example 1 using the appropriate starting material.

- 76 044109

Stage 63-2.

5-Bromo-1-(cyanomethyl)-7-fluoro-N-methyl-N-phenylindole-2-carboxamide (compound 63 c).

The title compound was prepared from compound 63b obtained in Step 63-1 by performing a step similar to Step 9-1 of Example 9 using an appropriate reagent.

LC/MS mass spectrometry: m/z 386 ([M+H]+).

LC/MS retention time: 3.17 min (analytical conditions: SMD-FA10-long).

Stage 63-3.

5-Bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-7-fluoro-N-methyl-N-phenylindole-2-carboxamide (compound 63 d).

The title compound was prepared from compound 63 c obtained in step 632 by performing a step similar to step 1-6 of example 1 using the appropriate starting material. LC/MS mass spectrometry: m/z 426 ([M+H]+).

LC/MS retention time: 1.36 min (analytical conditions: SMD-FA05-1). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.75 (1H, s), 7.43-7.30 (6H, m), 6.08 (1H, br.s), 3.44 ( 3H, s), 2.11-1.69 (3H, m) 1.40-1.35 (3H, m).

Stage 63-4.

1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-7-fluoro-N-methyl-5-(oxan-4-yl)-N-phenylindole-2carboxamide (compound 63E).

The title compound was prepared from compound 63 d obtained in step 63-3 and zinc (II) (tetrahydro-2H-pyran-4-yl) iodide (compound 8a) by performing a step similar to step 8-1 of example 8 , using the appropriate starting material.

LC/MS mass spectrometry: m/z 432 ([M+H]+).

LC/MS retention time: 1.22 min (analytical conditions: SMD-FA05-1).

Stage 63-5.

7-Φτορ-Ν-methyl-1-[(1 S,2S)-2-methyl-1 -(5-oxo-4H-1,2,4-oxadiazol-3 -yl)cyclopropyl]-5 -(oxane -4yl)-N-phenylindole-2-carboxamide (compound 63f).

The title compound was prepared from Compound 63e obtained in Step 63-4 by performing a step similar to Steps 1-8 of Example 1 using the appropriate starting material. LC/MS mass spectrometry: m/z 491 ([M+H]+).

LC/MS retention time: 1.21 min (analytical conditions: SQD-FA05-01).

Stage 63-6.

7-fluoro-1-[(1 S,2S)-2-methyl-1 -(5-oxo-4H-1,2,4-oxadiazol-3 -yl)cyclopropyl]-5 -(oxan-4-yl )indole2-carboxylic acid (compound 63 g).

The title compound was prepared from compound 63f obtained in step 63-5 by performing a step similar to step 6-4 of example 6 using the appropriate starting material. LC/MS mass spectrometry: m/z 402 ([M+H]+).

LC/MS retention time: 0.97 min (analytical conditions: SMD-FA05-1).

Compound 64b used in the synthesis of Example 64 was prepared using the following method.

Chemical formula 59

Stage 64-1.

tert-Butyl-(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[2-oxo-3-[1-[(3R)-oxolan-3-yl]indazole -5yl]imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 64a).

The title compound was prepared from compound 11k obtained in Step 11-7 and compound 8f obtained in Step 8-4 by performing a step similar to Step 1-11 of Example 1 using the corresponding starting material.

LC/MS mass spectrometry: m/z 628 ([M+H]+).

LC/MS retention time: 1.32 min (analytical conditions: SMD-FA05-1).

Stage 64-2.

1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3c]pyridin-3-yl]-3-[ hydrochloride 1-[(3R)-oxolan-3-yl]indazol-5-yl]imidazol-2-one (compound 64b).

The title compound was prepared from compound 64a obtained in step 64-1 by performing a step similar to step 11-8 of example 11 using the appropriate reagent.

LC/MS mass spectrometry: m/z 528 ([M+H]+).

LC/MS retention time: 0.78 min (analytical conditions: SMD-FA05-1).

Compound 65c used in the synthesis of Example 65 was prepared using the following method.

Chemical formula 60

Stage 65-1.

tert-Butyl (4 S)-2-(4-chloro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1 yl]-4 -methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 65b).

The title compound was prepared starting from compound 42e obtained in step 42-4 and 5-bromo-4-fluoro-1-methylindazole (compound 65a) by performing a step similar to step 1-11 of example 1 using the corresponding starting material substances.

LC/MS mass spectrometry: m/z 606 ([M+H]+).

LC/MS retention time: 1.38 min (analytical conditions: SMD-FA05-1).

Stage 65-2.

1-[(4S)-2-(4-chloro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3c]pyridin-3-yl]-3 hydrochloride 4-fluoro-1-methylindazol-5-yl)imidazol-2-one (compound 65 c).

The title compound was prepared from compound 65b obtained in step 65-1 by performing a step similar to step 11-8 of example 11 using the appropriate reagent.

LC/MS mass spectrometry: m/z 506 ([M+H]+).

LC/MS retention time: 0.86 min (analytical conditions: SMD-FA05-1).

Compound 67b used in the synthesis of Example 67 was prepared using the following method.

Chemical formula 61

Stage 67-1.

tert-Butyl (48)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol1-yl]-4-methyl -6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 67a).

The title compound was prepared starting from compound 11k obtained in step 11-7 and 5-bromo-4-fluoro-1-methylindazole (compound 65a) by performing a step similar to step 1-11 of example 1 using the corresponding starting material substances.

LC/MS mass spectrometry: m/z 590 ([M+H]+).

LC/MS retention time: 1.31 min (analytical conditions: SMD-FA05-1).

Stage 67-2.

1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3c]pyridin-3-yl]-3-( hydrochloride 4-fluoro-1-methylindazol-5-yl)imidazol-2-one (compound 67b).

The title compound was prepared from compound 67a obtained in step 67-1 by performing a step similar to step 11-8 of example 11 using the appropriate reagent.

LC/MS mass spectrometry: m/z 490 ([M+H]+).

LC/MS retention time: 0.80 min (analytical conditions: SQD-FA05-1).

Compound 68c used in the synthesis of Example 68 was prepared using the following method.

- 78 044109

Chemical formula 62

Stage 68-1.

tert-Butyl (4S)-3-[3-(4-chloro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5 dimethylphenyl)-4- methyl 6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 68b).

The title compound was prepared starting from compound 11k obtained in step 11-7 and 5-bromo-4-chloro-1-methylindazole (compound 68a) by performing a step similar to step 1-11 of example 1 using the appropriate starting material .

LC/MS mass spectrometry: m/z 606 ([M+H]+).

LC/MS retention time: 1.34 min (analytical conditions: SMD-FA05-1).

Stage 68-2.

1-(4-chloro-1-methylindazol-5-yl)-3-[(48)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7tetrahydropyrazolo hydrochloride [ 4,3-c]pyridin-3-yl]imidazol-2-one (compound 68c).

The title compound was prepared from compound 68b obtained in step 68-1 by performing a step similar to step 11-8 of example 11 using the appropriate reagent.

LC/MS mass spectrometry: m/z 506 ([M+H] ⁺ ).

LC/MS retention time: 0.83 min (analytical conditions: SMD-FA05-1).

Compound 69b used in the synthesis of Example 69 was prepared using the following method.

Chemical formula 63

Stage 69-1.

tert-Butyl (4S)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3-methylphenyl)4-methyl- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 69a).

The title compound was prepared starting from compound 46d obtained in step 46-3 and 5-bromo-4-fluoro-1-methylindazole (compound 65a) by performing a step similar to step 1-11 of example 1 using the appropriate starting material .

LC/MS mass spectrometry: m/z 576 ([M+H] ⁺ ).

LC/MS retention time: 1.25 min (analytical conditions: SMD-FA05-1).

Stage 69-2.

1-(4-Fluoro-1-methylindazol-5-yl)-3-[(4S)-2-(4-fluoro-3-methylphenyl)-4-methyl-4,5,6,7tetrahydropyrazolo[4, 3-c]pyridin-3-yl]imidazol-2-one (compound 69b).

The title compound was prepared from compound 69a obtained in step 69-1 by performing a step similar to step 11-8 of example 11 using the appropriate reagent.

LC/MS mass spectrometry: m/z 476 ([M+H] ⁺ ).

LC/MS retention time: 0.77 min (analytical conditions: SMD-FA05-1).

Compound 70c used in the synthesis of Example 70 was prepared using the following method.

- 79 044109

Chemical formula 64

Stage 70-1.

tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(6-fluoro-1-methylindazol-5-yl)-2-oxoimidazol1 -yl]-4-methyl -6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 7 0b).

The title compound was prepared starting from compound 11k obtained in step 11-7 and 5-bromo-6-fluoro-1-methylindazole (compound 70a) by performing a step similar to step 1-11 of example 1 using the corresponding starting material substances.

LC/MS mass spectrometry: m/z 590 ([M+H]+).

LC/MS retention time: 1.28 min (analytical conditions: SMD-FA05-1).

Stage 70-2.

1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3c]pyridin-3-yl]-3 -( hydrochloride 6-fluoro-1-methylindazol-5-yl)imidazol-2-one (compound 70c).

The title compound was prepared from compound 70b obtained in step 70-1 by performing a step similar to step 11-8 of example 11 using the appropriate starting material.

LC/MS mass spectrometry: m/z 490 ([M+H]+).

LC/MS retention time: 0.81 min (analytical conditions: SMD-FA05-1).

Compound 71b used in the synthesis of Example 71 was prepared using the following method.

Chemical formula 65

Stage 71-1.

5-Bromo-6-fluoro-1-(2-methoxyethyl)indazole (compound 71b).

The title compound was prepared from 5-bromo-6-fluoro-1H-indazole (compound 71a) by performing a step similar to step 8-4 of Example 8 using the appropriate starting material.

LC/MS mass spectrometry: m/z 273 ([M+H]+).

LC/MS retention time: 1.06 min (analytical conditions: SMD-FA05-1).

Stage 71-2.

tert-Butyl (48)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[6-fluoro-1-(2-methoxyethyl)indazol-5-yl]-2oxoimidazol-1 -yl ]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (compound 71c).

The title compound was prepared from Compound 11k obtained in Step 11-7 and Compound 71b obtained in Step 71-1 by performing a step similar to Steps 1-11 of Example 1 using an appropriate reagent.

LC/MS mass spectrometry: m/z 634 ([M+H]+).

LC/MS retention time: 1.30 min (analytical conditions: SMD-FA05-1).

Stage 71-3.

1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3c]pyridin-3-yl]-3-[ hydrochloride 6-fluoro-1-(2-methoxyethyl)indazol-5-yl]imidazol-2-one (compound 71d).

The title compound was prepared from compound 71c obtained in step 71-2,

- 80 044109 by carrying out a step similar to step 11-8 of example 11, using the appropriate starting material.

LC/MS mass spectrometry: m/z 534 ([M+H]+).

LC/MS retention time: 0.83 min (analytical conditions: SMD-FA05-1).

Example 73. Synthesis of 3-[(1S,2S)-1-[5-(2-ethyl-3-methylpyridin-4-yl)-2-[(4S)-2-(4-fluoro-3,5dimethylphenyl) -4-methyl-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3c]pyridin-5-carbonyl]indole -1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 73).

Stage 73-1.

Chemical formula 66

To a solution of the racemic form (compound 73a, 29.6 mg, 0.058 mmol) in DMF (1.5 ml), synthesized using a method similar to the method for preparing the compound in step 61-2, and compound 1o (26.8 mg, 0.064 mmol) obtained in step 1-9, HATU (26.6 mg, 0.070 mmol) and N,Ndiisopropylethylamine (18.1 mg, 0.14 mmol) were added and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with ethyl acetate and washed with distilled water. The organic layer was evaporated under reduced pressure to obtain a residue which was a mixture of stereoisomers. The stereoisomers were separated by reverse phase HPLC to give compound A (14.5 mg, 29% yield) and compound B (15.5 mg, 31% yield), which is a white, solid, title compound 73. Separation Conditions.

Column: YMC Actus ODS-A, 20x100 mm, 5 µm.

Solvent: 0.1% aqueous solution of formic acid/0.1% solution of formic acid and acetonitrile = 40/60 (homogeneous system).

Flow rate: 20 ml/min, room temperature.

Compound A.

LC/MS mass spectrometry: m/z 872 ([M+H] ⁺ ).

LC/MS retention time: 0.99 min (analytical conditions: SMD-FA05-3).

Compound B (compound 73).

LC/MS mass spectrometry: m/z 872 ([M+H] ⁺ ).

LC/MS retention time: 1.01 min (analytical conditions: SMD-FA05-3).

Example 74. Synthesis of 3-[(1S,2S)-1-[6-fluoro-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3- (1methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(2methoxy-3-methylpyridin-4 -yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 74).

- 81 044109

Chemical formula 67

Stage 74-1.

5-Bromo-6-fluoro-N-methyl-N-phenyl-1H-indole-2-carboxamide (compound 74b).

The title compound was prepared from 5-bromo-6-fluoro-1H-indole-2-carboxylic acid (compound 74a) by performing a step similar to steps 1-10 of Example 1 using the appropriate starting material.

LC/MS mass spectrometry: m/z 347 ([M+H]+).

LC/MS retention time: 1.06 min (analytical conditions: SMD-TFA05-4).

Stage 74-2.

5-Bromo-1-(cyanomethyl)-6-fluoro-X-methyl-X-phenylindole-2-carboxamide (compound 74c).

The title compound was prepared from compound 74b obtained in step 74-1 by performing a step similar to step 9-1 of example 9 using the appropriate reagent.

LC/MS mass spectrometry: m/z 386 ([M+H]+).

LC/MS retention time: 1.06 min (analytical conditions: SMD-TFA50-4).

Stage 74-3.

5-Bromo-1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-6-fluoro-N-methyl-N-phenylindole-2-carboxamide (compound 74d).

The title compound was prepared from compound 74c obtained in step 74-2 and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (compound 1k) by performing a step similar to step 1 -6 example 1 using the appropriate reagent.

LC/MS mass spectrometry: m/z 426 ([M+H]+).

LC/MS retention time: 1.04 min (analytical conditions: SMD-FA10-5).

Stage 74-4.

5-Bromo-6-fluoro-N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-Nphenylindole -2-carboxamide (compound 74e).

The title compound was prepared from compound 74d obtained in step 74-3 by performing a step similar to step 1-8 of example 1 using the appropriate starting material.

LC/MS mass spectrometry: m/z 485 ([M+H]+).

LC/MS retention time: 1.33 min (analytical conditions: SMD-FA05-1).

Stage 74-5.

5-Bromo-6-fluoro-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2carboxylic acid (compound 74f).

The title compound was prepared from compound 74e obtained in step 74-4,

- 82 044109 by carrying out a stage similar to stage 6-4 of example 6, using the appropriate starting material.

LC/MS mass spectrometry: m/z 396 ([M+H]+).

LC/MS retention time: 0.80 min (analytical conditions: SQD-FA05-1).

Stage 74-6.

3-[(1S,2S)-1-[5-bromo-6-fluoro-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3- (1-methylindazol-5yl)-2-oxoimidazol-1 -yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1 -yl]-2methylcyclopropyl]-4H -1,2,4-oxadiazol-5-one (compound 74 g).

The title compound was prepared from compound 74f obtained in step 74-5 and compound 61b obtained in step 61-2 by performing a step similar to steps 1-10 of example 1 using the appropriate reagent. LC/MS mass spectrometry: m/z 849 ([M+H]+).

LC/MS retention time: 1.42 min (analytical conditions: SMD-FA05-1).

Stage 74-7.

3-[(1S,2S)-1-[6-fluoro-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methylindazole -5-yl)-2oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(2-methoxy-3-methylpyridin 4-yl) indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 74).

The title compound was synthesized by a similar step to Step 6-5 of Example 6 using compound 74g obtained from Step 74-6 and 4-iodo-2methoxy 3-methylpyridine (compound 6g) and a suitable reagent.

LC/MS mass spectrometry: m/z 892 ([M+H]+).

LC/MS retention time: 1.48 min (analytical conditions: SMD-TFA05-1).

Examples 75-77.

A step similar to Step 8-1 of Example 8 was carried out using an indole bromide compound and an iodo(oxan-4-yl)zinc derivative and a corresponding reagent to prepare the compounds of Examples 75-77 illustrated in Table 2-6 by the following reaction.

Chemical formula 68

- 83 044109

Table 2-6

Resultant compounds of Examples 75-77

Example No. Structure Compound Analytical conditions LC/MS retention time (min.) LC/MS mass spectrometry (m/z) 75 aw L k 3-[(lS,2S)-l-[2-[2-(4fluoro-3,5-dimethylphenyl)3-[3-(1-methylindazol-5yl)-2-oxoimidazol-1 yl]-6,7 -dihydro-4Hpyrazolo[4,3 -c]pyridin5-carbonyl]-5-(6oxaspiro[4,5]decan-9yl)indol-1 -yl]-2methylcyclopropyl]-4H1,2,4-oxadiazol-5-one SMDTFA05-2 1.57 878 ([M+H] ⁺ ) 76 0W > G 3-[(lS,2S)-l-[5-(2,2dimethyloxan-4-yl)-2-[2(4-fluoro-3,5dimethylphenyl)-3-[3-[1-(2-methoxyethyl )indazol5 -yl] -2-oxoimidazol-1 yl]-6,7-dihydro-4Hpyrazolo[4,3 -c] pyridin5 -carbonyl] indol-1 -yl] 2-methylcyclopropyl] 4H-1,2,4- oxadiazol-5-one SMDTFA05-2 1.44 895 ([M+H] ⁺ ) 77 1 F gch Λ X Г> ......( \) ml 3-[(lS,2S)-l-[5-[(2S, 4S)(2-ethyloxan-4-yl)-2-[2(4-fluoro-3,5- dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1-yl]-6,7dihydro-4H- pyrazolo[4,3 -с] pyridin5 -carbonyl] indol-1 -yl] 2-methylcyclopropyl] 4H-1,2,4-oxadiazol-5-one SMDTFA05-2 1.51 851 ([m+n] ⁺ )

Compound 75b used in the synthesis of Example 75 was prepared by the following method.

Stage 75-1.

Iodo(6-oxaspiro[4,5]decan-9-yl)zinc (compound 75b).

Chemical formula 69

75a 75b

The title compound was prepared from 9-iodo-6-oxaspiro[4,5]decane (compound 75a) by a similar step to Step 41-1 of Example 41 using the appropriate reagent.

The compound was directly used in the next step.

Compound 76a used in the synthesis of Example 76 was prepared by the following method.

- 84 044109

Chemical formula 70

Stage 76-1.

3-[(1S,2S)-1-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-[1-(2-methoxyethyl)indazole-5- yl]-2oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2methylcyclopropyl]-4H-1,2,4- Oxadiazol-5-one (compound 76a).

The title compound was prepared from compound 56b obtained in step 56-1 and compound 6f obtained in step 6-4 by performing a step similar to steps 1-10 of Example 1 using the appropriate reagent.

LC/MS mass spectrometry: m/z 861 ([M+H]+).

LC/MS retention time: 1.45 min (analytical conditions: SMD-FA05-2).

Example 77.

Chemical formula 71

Stage 77-1.

2-ethyl-4-iodoxane (compound 77b).

To a solution of but-3-en-1-ol (0.588 ml, 6.93 mmol) in acetic acid (2.48 ml), propionaldehyde (0.650 ml, 9.01 mmol) and lithium iodide (2.78 g) were added sequentially , 20.8 mmol), and the mixture was stirred at 60°C for 1 hour. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium hydrogen carbonate, then dried over magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure (lower limit was 150 hPa) and the residue was purified by silica gel chromatography (ethyl acetate/hexane=0:1 to 1:9) to obtain the title compound 77b as a pale yellow oily mixture of diastereomers (1.12 g, 67% yield, syn:anti=1.00:0.45).

¹ H-NMR (400 MHz, CDCl ₃ ):

syn δ: 4.31-4.23 (1H, m), 3.90-3.82 (1H, m), 3.44-3.37 (1H, m), 3.21-3.15 ( 1H, m), 2.37-1.38 (6H, m), 0.92 (3H, t, J=7.4 Hz);

anti δ: 4.87-4.84 (1H, m), 3.90-3.82 (2H, m), 3.70-3.64 (1H, m), 2.37-1.38 ( 6H, m), 0.94 (3H, t, J=7.6 Hz).

Stage 77-2.

(2-ethyloxan-4-yl)iodozinc (compound 77c).

To a solution of zinc (102 mg, 1.56 mmol) in DMA (0.25 mL), a mixture of chloro(trimethyl)silane (0.017 mL, 0.137 mmol) and 1,2-dibromoethane (0.012 mL, 0.137 mmol) was slowly added dropwise. under a nitrogen atmosphere while maintaining the temperature at 65°C or lower, and the mixture was stirred at room temperature for 15 minutes. Then, a solution of compound 77b (300 mg, 1.25 mmol) in DMA (0.625 ml) obtained in step 77-1 was slowly added dropwise to the mixture, maintaining the temperature at 65 °C or lower, and the mixture

- 85 044109 was stirred under nitrogen at room temperature for 30 minutes to obtain a solution of the diastereomer mixture in DMA (0.86 M) of the title compound 77c.

Stage 77-3.

3-[(1S,2S)-1-[5-(2-ethuloxan-4-ul)-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole -5-yl)-2oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2methylcyclopropyl]-4H-1,2 ,4-oxadiazol-5-one (compound 77).

Palladium (II) acetate (2.20 mg, 0.00978 mmol) and 2-(2- dicyclohexylphosphanylphenyl)-1-^ 1-N, 3-N, 3-N-tetramethylbenzene-1,3-diamine (8.54 mg, 0.020 mmol), and the mixture was removed from air under reduced pressure, then the vessel was filled with nitrogen, and the mixture was stirred at room temperature for 5 minutes. A solution of compound 77c in DMA (0.86 M, 0.398 mL, 0.342 mmol) obtained in step 77-2 was then added and the mixture was stirred at room temperature for 1.5 hours. Formic acid was added to the reaction mixture and the reaction mixture was purified reverse phase chromatography on silica gel (acetonitrile/water, 0.1% formic acid) to obtain a mixture of syn-type diastereomers. The mixture of syn-type diastereomers was separated into stereoisomers by reverse phase HPLC to give white, amorphous A (17.4 mg, 41% yield) and white, amorphous B (14.9 mg, 37% yield) as the title compound. 77.

Conditions of separation.

Column: CHIRALCEL OD-RH 5 µm, 4.6 mm x 150 mm (Daicel).

Solvent: 0.1% aqueous formic acid solution/0.1% formic acid solution and acetonitrile = 20/80 (homogeneous system).

Flow rate: 1.0 ml/min, room temperature.

Compound A.

LC/MS mass spectrometry: m/z 851 ([M+H]+). HPLC retention time: 4.99 min (separation condition). LC/MS retention time: 1.46 min (analytical conditions: SMD-FA05-1).

Compound B (compound 77) LC/MS mass spectrometry: m/z 851 ([M+H] ⁺ ). HPLC retention time: 6.64 min (separation condition). LC/MS retention time: 1.46 min (analytical conditions: SMD-FA05-1).

Example 78. Synthesis of 3-[(1S,2S)-2-ethyl-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5yl)- 2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4-yl)indol-1yl]cyclopropyl]-4H- 1,2,4-oxadiazol-5-one (compound 78).

Chemical formula 72

Stage 78-1.

2-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6, 7dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]acetonitrile (compound 78a).

The title compound was prepared starting from compound 51c obtained in step 51-3 and 5-bromo-1-(cyanomethyl)indole-2-carboxylic acid (compound 6a) by performing a step similar to step 1-10 of example 1, using the appropriate starting material.

LC/MS mass spectrometry: m/z 718 ([M+H]+).

LC/MS retention time: 1.30 min (analytical conditions: SMD-FA05-1).

Stage 78-2.

- 86 044109

2-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro4H- pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]acetonitrile (compound 78b).

The title compound was prepared starting from compound 78a obtained in step 78-1 and zinc(II) (tetrahydro-2H-pyran-4-yl)iodide (compound 8a) by performing a step similar to step 8-1 of example 8, using the appropriate starting material.

LC/MS mass spectrometry: m/z 724 ([M+H]+).

LC/MS retention time: 1.21 min (analytical conditions: SMD-FA05-1).

Stage 78-3.

(1S,2S)-2-ethyl-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1yl ]-6,7-dihydro-4H-pyrazolo [4,3-c]pyridin-5-carbonyl] -5 -(oxan-4-yl)indol-1 -yl] cyclopropan-1 carbonitrile (compound 78d).

The title compound was prepared from 78b obtained in Step 78-2 by performing a step similar to Steps 1-6 of Example 1 using the appropriate reagent.

LC/MS mass spectrometry: m/z 778 ([M+H]+).

LC/MS retention time: 1.27 min (analytical conditions: SMD-FA05-RP).

Stage 78-4.

3-[(1S,2S)-2-ethyl-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2- oxoimidazol-1yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl] -5 -(oxan-4-yl)indol-1 -yl] cyclopropyl] -4H1,2, 4-oxadiazol-5-one (compound 78).

The title compound was prepared from 78d obtained in Step 78-2 by performing a step similar to Steps 1-8 of Example 1 using the appropriate starting material.

LC/MS mass spectrometry: m/z 837 ([M+H]+).

LC/MS retention time: 1.39 min (analytical conditions: SMD-TFA05-2).

Example 79. Synthesis of 3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2oxoimidazol- 1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2(hydroxymethyl)cyclopropyl] -4H-1,2,4-oxadiazol-5-one (compound 79).

Chemical formula 73

Stage 79-1.

5-Bromo-1-[(1S,2S)-1-cyano-2-(phenylmethoxymethyl)cyclopropyl]-N-methyl-N-phenylindole-2carboxylic acid (compound 79b).

The title compound was prepared starting from compound 6c obtained in step 6-1 and 2,2-dioxide (4R)-4-(phenylmethoxymethyl)-1,3,2-dioxathiolane (compound 79a) by performing a step similar to step 1-6 of example 1 using the appropriate starting material.

LC/MS mass spectrometry: m/z 514 ([M+H]+).

- 87 044109

LC/MS retention time: 1.48 min (analytical conditions: SMD-FA05-1).

Stage 79-2.

1-[(1S,2S)-1-cyano-2-(phenylmethoxymethyl)cyclopropyl]-N-methyl-5-(oxan-4-yl)-N-phenylindole-2carboxylic acid (compound 79C).

The title compound was prepared from compound 79b obtained in step 79-1 and zinc(II) (tetrahydro-2H-pyran-4-yl)iodide (compound 8a) by performing a step similar to step 8-1 of example 8. using the appropriate starting material.

LC/MS mass spectrometry: m/z 520 ([M+H]+).

LC/MS retention time: 1.37 min (analytical conditions: SMD-FA05-1).

Stage 79-3.

K-methyl-5-(oxan-4-yl)-1 -[(1 S,2S)-1 -(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-(phenylmethoxymethyl ) cyclopropyl]-C-phenylindole-2-carboxamide (compound 79d).

The title compound was prepared from compound 79c obtained in step 79-2 by performing a step similar to step 1-8 of example 1 using the appropriate reagent.

LC/MS mass spectrometry: m/z 579 ([M+H]+).

LC/MS retention time: 1.37 min (analytical conditions: SMD-FA05-1).

Stage 79-4.

5-(okсαн-4-ul)-1-[(1S,2S)-1-(5-okсo-4Н-1,2,4-okсαдuαzol-3-yl)-2(phenylmethoxymethyl)cyclopropyl]indole -2 -carboxylic acid (compound 79e).

The title compound was prepared from compound 79d obtained in step 79-3 by performing a step similar to step 6-4 of example 6 using the appropriate starting material.

LC/MS mass spectrometry: m/z 490 ([M+H]+).

LC/MS retention time: 1.12 min (analytical conditions: SMD-FA05-1).

Stage 79-5.

3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1- yl]-6,7dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2(phenylmethoxymethyl)cyclopropyl]-4H-1 ,2,4-oxadiazol-5-one (compound 79f).

The title compound was prepared from compound 79e obtained in step 79-4 and compound 51c obtained in step 51-3 by performing a step similar to steps 1-10 of example 1 using the corresponding starting material.

LC/MS mass spectrometry: m/z 929 ([M+H]+).

LC/MS retention time: 1.41 min (analytical conditions: SMD-FA05-1).

Stage 79-6.

3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1- yl]-6,7dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2(hydroxymethyl)cyclopropyl]-4H-1 ,2,4-oxadiazol-5-one (compound 79).

A solution of compound 79F (35.4 mg, 0.0381 mmol) in dichloromethane (0.762 ml) obtained in step 79-5 was cooled to 0° C. and a hexane solution (0.191 ml, 0.191 mmol) of 1M boron trichloride was slowly added. The reaction solution was warmed to room temperature and stirred for 105 minutes, and then a saturated sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted using dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution and dried with sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure and the residue was purified by reverse phase column chromatography (acetonitrile/water, 0.1% formic acid) to give the title compound (18.5 mg, 50% yield).

LC/MS mass spectrometry: m/z 839 ([M+H]+).

LC/MS retention time: 1.20 min (analytical conditions: SMD-TFA05-1).

Example 80. Synthesis of 3-[(1S,2S)-1-[2-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-[3- (1methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5(oxan-4-yl)indol- 1 -yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 80).

- 88 044109

Chemical formula 74

Stage 80-1.

Ethyl (E)-3-[[(2S)-1-cyanopropan-2-yl]amino]but-2-enoate (compound 80c).

Ethyl 3-oxobutanoate (compound 80a, 13 g, 99.9 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction solution was evaporated under reduced pressure and the solvent was evaporated, and then the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 3:2) to give the title compound 80c (9.5 g, 58% yield) as a yellow oil.

LC/MS mass spectrometry: m/z 197 ([M+H]+).

LC/MS retention time: 0.86 min (analytical conditions: SMD-FA10-1).

Stage 80-2.

Ethyl 3-[[(2S)-1-cyanopropan-2-yl]amino]butanoate (compound 80d) To a solution of compound 80c (10 g, 51.0 mmol) in dichloromethane (200 ml) obtained in step 80-1 , and sodium triacetoxyborohydride (43.3 g, 204 mmol), acetic acid (3 ml) was added, and the mixture was stirred at room temperature for 16 hours. Water and acetic acid were added to the reaction solution, the pH was adjusted to 5, and then the aqueous layer was extracted using ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried using sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 1:4) to give the title compound 80d (5.5 g, 54% yield) as yellow oil-like substance.

LC/MS retention time: 0.83 min (analytical conditions: SMD-FA10-4).

Stage 80-3.

(6S)-1-formyl-4-hydroxy-2,6-dimethyl-3,6-dihydro-2H-pyridine-5-carbonitrile (compound 80e).

A toluene (5 ml) solution of compound 80d (1.0 g, 5.04 mmol) obtained in step 80-2 was slowly added dropwise at 80°C to a toluene (10 ml) solution of potassium tert-butoxide (680 mg, 6.06 mmol). After stirring the solution at 80°C for 1 hour, the solution was cooled to room temperature to obtain a solution of (6S)-4-hydroxy-2,6-dimethyl-1,2,3,6-tetrahydropyridine-5-carbonitrile in toluene.

A toluene (5 ml) solution of acetic anhydride (12.1 g, 118 mmol) was slowly added dropwise to a solution of formic acid (7.26 g) at 0°C and stirred at 0°C for 30 min, and then slowly A toluene solution of the resulting (6S)-4-hydroxy-2,6-dimethyl-1,2,3,6tetrahydropyridine-5-carbonitrile was added dropwise. After stirring the reaction solution at 110°C for 16 hours, it was cooled to room temperature and evaporated under reduced pressure to remove the solvent by evaporation, and a mixture (1.3 g) containing the title compound 80e was obtained as an oil.

Stage 80-4.

(4S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5carbaldehyde (compound 80f ).

A solution of compound 80e (1.30 g, 7.21 mmol) in ethanol (30 ml) obtained from step 80-3 and (4-fluoro-3,5-dimethylphenyl)hydrazine hydrochloride (compound 2c, 690 mg, 3 .62 mmol) was heated to 75°C and stirred for 16 hours. The reaction solution was cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1:0 to 9:1) and the title compound 80f (2 steps from step 80-3, 800 mg, 35% yield) was obtained as a yellow solid.

LC/MS mass spectrometry: m/z 317 ([M+H]+).

LC/MS retention time: 0.79 min (analytical conditions: SMD-FA10-3).

Stage 80-5.

1-(2,2-dimethoxyethyl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-5-formyl-4,6-dimethyl-6,7-dihydro-4Hpyrazolo[4 ,3-c]pyridin-3-yl]urea (compound 80 g).

2,2-Dimethoxyethane-1-amine (1.14 g, 10.8 mmol) was added at 0°C to a solution of N,N'carbodiimidazole (1.63 g, 10.1 mmol) in DMA (50 ml), and the resulting mixture was stirred for 30 minutes. Potassium tert-butoxide (5.62 g, 50.1 mmol) and compound 80f (2.64 g, 8.34 mmol) obtained in step 80-4 were sequentially added to the solution. After stirring the mixture at room temperature for 6 hours, water was added and the aqueous layer was extracted using ethyl acetate. After the organic layer was washed with a saturated sodium chloride aqueous solution, it was dried with sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure to obtain the title compound 80 g (2.80 g, 75% yield) as a brown oil.

LC/MS mass spectrometry: m/z 448 ([M+H]+).

LC/MS retention time: 0.84 min (analytical conditions: SMD-FA10-2).

Stage 80-6.

(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4Hpyrazolo [4,3-c]pyridine-5-carbaldehyde (compound 80h).

A solution of compound 80g (2.50 g, 5.59 mmol) in DMF (30 ml) obtained in step 80-5 and 4methylbenzenesulfonic acid (1.06 g, 6.16 mmol) was heated to 80°C and stirred for 2 hours. After cooling the solution to room temperature, water was added and the aqueous layer was extracted using ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried with sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 3:1) to obtain a diastereomer mixture (480 mg) containing the title compound (Compound 80h) as a white solid.

LC/MS mass spectrometry: m/z 384 ([M+H]+).

LC/MS retention time: 1.64 min (analytical conditions: SMD-TFA05-6). A mixture of diastereomers (480 mg, 5.59 mmol) containing the title compound (compound 80h: (4S,6R)-2(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-(2 -oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3c]pyridine-5-carbaldehyde) was separated into stereoisomers by SPC to give compound A

- 90 044109 (155 mg, 7.0% yield), which is compound 80h and compound B (270 mg, 12% yield).

Conditions for the division of agricultural holdings.

Column: CHIRALPAK AD-H, 50x500 mm, 3 µm (Daicel).

Solvent: supercritical carbon dioxide/ethanol=70:30 (homogeneous system).

Flow rate: 150 ml/min, 35°C.

Detected wavelength: 254 nm.

Connection A (connection 80h).

SFC retention time: 4.07 min.

LC/MS mass spectrometry: m/z 384 ([M+H]+).

LC/MS retention time: 2.15 min (analytical conditions: SMD-FA1060-1).

Ή-NMR (300 MHz, DMSO-d ₆ ) δ: 10.35 (1H, s), 8.24 (1H, s), 7.11 (2H, d, J=6.3 Hz), 6, 60-6.58 (2H, m) 5.21-5.14 (1H, m), 4.46-4.21 (1H, m), 2.96-2.89 (1H, m), 2 .74-2.68 (1H, m), 2.20 (6H, s), 1.27-1.13 (6H, m).

It should be noted that compound 80h was identified as an R-isomer based on the result obtained by 2D-NOESY that its steric configuration is cis-configuration.

Compound B.

SFC retention time: 5.60 min.

LC/MS mass spectrometry: m/z 384 ([M+H]+).

LC/MS retention time: 2.16 min (analytical conditions: SMD-FA1060-1).

Ή-NMR (300 MHz, DMSO-d6) δ: 10.35 (1H, s), 8.31 (1H, s), 7.08 (2H, d, J=6.3 Hz), 6.61 -6.54 (2H, m) 5.39 (1H, kV, J=6.9 Hz), 3.89-3.84 (1H, m), 2.90 (1H, dd, J=3, 3, 15.6 Hz), 2.59-2.51 (1H, m), 2.20 (6H, d, J=2.1 Hz), 1.55 (3H, d, J=6.6 Hz), 1.18 (3H, d, J=6.6 Hz).

Stage 80-7.

3-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3yl]- 1H-imidazol-2-one (compound 80i).

A 5M sodium hydroxide solution (0.261 ml) was added to an ethanol solution (1.0 ml) of compound 80h (100 mg, 0.261 mmol) obtained in step 80-6, and the resulting mixture was stirred at 80°C for 10 hours. Cooling the mixture to room temperature and stirring for 60 hours, saturated aqueous ammonium chloride was added and the mixture was extracted using ethyl acetate to synthesize the title compound 80i (79%, 73 mg) as a white solid.

LC/MS mass spectrometry: m/z 356 ([M+H]+).

LC/MS retention time: 0.44 min (analytical conditions: SQD-FA05-2).

Stage 80-8.

1-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3yl]- 3-(1-methylindazol-5-yl)imidazol-2-one (compound 800j).

Copper(I) iodide (4.02 mg, 0.021 mmol) was added at room temperature to a suspension of Nmethylpiperazine (0.188 ml) of compound 80i (15 mg, 0.042 mmol) obtained in step 80-7, 5-bromo-1methylindazole (compound 1q , 10.7 mg, 0.051 mmol), (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (6.00 mg, 0.042 mmol) and potassium carbonate (17.5 mg, 0.127 mmol), and the mixture was stirred under a nitrogen atmosphere at 130°C for 90 minutes. The reaction mixture was purified by reverse phase chromatography on silica gel (acetonitrile/water, 0.1% formic acid) and evaporated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and extraction was carried out using ethyl acetate, and then the organic layer was evaporated under reduced pressure to obtain the title compound 80j (17.4 mg, 85% yield).

LC/MS mass spectrometry: m/z 486 ([M+H]+).

LC/MS retention time: 0.51 min (analytical conditions: SQD-FA05-2).

Stage 80-9.

2-trimethylsilylethoxymethyl 5-(oxan-4-yl)-1-[1S,2S)-2-[5-oxo-4-(2-trimethylsilylethoxymethyl)1,2,4-oxadiazol-3-yl]-2- methylcyclopropyl]indole-2-carboxylate (compound 80k).

To a solution of compound 8b (100 mg, 0.261 mmol) in DMF (2.6 ml) obtained in step 8-1 was added 55 wt.% sodium hydride (34.1 mg, 0.782 mmol) and 2-(trimethylsilyl) ethoxymethyl chloride (0.116 ml, 0.652 mmol) and the mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride solution was added and extraction was carried out using ethyl acetate. The residue obtained after concentration was then purified by normal phase column chromatography (ethyl acetate/hexane) to obtain the title compound 80k (147 mg, 88% yield) as a yellow gummy substance.

LC/MS retention time: 1.21 min (analytical conditions: SQD-FA05-2).

Stage 80-10.

5-(oxan-4-yl)-1-[(1S,2S)-1-[5-oxo-4-(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazol-3-yl]-2methylcyclopropyl]indole -2-carboxylic acid (80l).

A solution of compound 80k (147 mg, 0.228 mmol) in dichloromethane (2.3 ml) obtained in step 80-9 was added magnesium bromide/diethyl ether (295 mg, 1.14 mmol) and the mixture was stirred at 0°C in for 6.5 hours. The mixture was warmed to room temperature and stirred for 30 minutes, and then a saturated aqueous solution of ammonium chloride was added. It was then extracted using ethyl acetate and the resulting product was evaporated, and then the residue was diluted with DMSO and water, and purified by reverse phase chromatography (acetonitrile/water, 0.1% formic acid) to synthesize the title compound 801 (60 mg, yield 51 %).

LC/MS mass spectrometry: m/z 512 ([M-H] ^- ).

LC/MS retention time: 1.03 min (analytical conditions: SQD-FA05-2).

Stage 80-11.

5-(oxan-4-yl)-1-[(1S,2S)-2-[5-oxo-4-(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazol-3-yl]-2methylcyclopropyl]indole -2-carbonyl chloride (compound 80m).

To a solution of compound 801 (18 mg, 0.036 mmol) in acetonitrile (0.36 mL) obtained in step 80-10 was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0. 0057 mg, 0.043 mmol), and the mixture was stirred at room temperature for 2 hours and then evaporated to give the crude product of the title compound 80m. This compound was directly used in the next step.

Stage 80-12.

3-[(1S,2S)-2-[2-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-[3-(1-methylindazole -5-yl)-2oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4-yl)indol 1-yl] -2methylcyclopropyl]-4-(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazol-5-one (compound 80n).

Compound 80m, obtained in step 80-11, was dissolved in THF (0.717 ml), and compound 80j (19.1 mg, 0.036 mmol), obtained in step 80-8, and N,N-diisopropylethylamine (0.0188 ml, 0.108 mmol) was added to the solution, then the mixture was stirred at room temperature for 22 hours and then methanol and formic acid were added. The mixture was evaporated and the residue was diluted with DMSO and water and purified by reverse phase column chromatography (acetonitrile/water, 0.1% formic acid) to give the title compound 80n (32 mg, 91% yield).

LC/MS mass spectrometry: m/z 982 ([M+H]+).

LC/MS retention time: 1.12 min (analytical conditions: SQD-FA50-1).

Stage 80-13.

3-[(1S,2S)-1-[2-[(4S,6R)-2-(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-3-[3-(1-methylindazole -5-yl)-2oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4-yl)indol-1-yl ]-2methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 80).

To a THF solution (0.326 mL) of compound 80n (32 mg, 0.033 mmol) obtained in step 80-12 was added acetic acid (0.0019 mL, 0.033 mmol) and a THF solution (0.065 mL, 0.065 mmol) of 1 M tetrabutylammonium fluoride , and the mixture was stirred at 80°C for 66 hours. Acetic acid (0.0019 ml, 0.033 mmol) and a THF solution (0.065 ml, 0.065 mmol) of 1 M tetrabutylammonium fluoride were added, and the mixture was stirred for 23.5 hours. Next A solution of 1M tetrabutylammonium fluoride in THF (0.065 ml, 0.065 mmol) was added, then the mixture was stirred for 7 hours, and then formic acid was added. After concentration, the mixture was diluted with DMSO and water, and purified by reverse phase column chromatography (acetonitrile/water, 0.1% formic acid) to give the title compound 80 (18 mg, 65% yield).

LC/MS mass spectrometry: m/z 851 ([M+H]+).

LC/MS retention time: 1.42 min (analytical conditions: SMD-TFA05-1). Compounds of examples 101-159, illustrated in table. 2-7 below were obtained similarly to examples 1-80.

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Table 2-7

Resultant compounds of examples 101-159

Example No. Structure Compound Analytical conditions LC/MS retention time (min.) LC/MS mass spectrometry (m/z) 101 A\/N-U G\. ^/ hb ⁿ °L 3-[(18.28)-1-[5-(2-ethyl3-methylpyridin-4-yl)2-[2-(4-fluoro-3,5- dimethylphenyl)-3-[3-[1(2- methoxyethyl)ind azol-5 yl]-2-oxoimid azol-1 yl]-6,7-d ihydro-4Hpyrazolo[4,3c]pyridine-5- carbonyl]indol-1-yl]2-methylcyclopropyl]4H-1,2,4-oxadiazol-5one SMDTFA05-3 1.16 902 ([M+H] ⁺ ) 102 P 1 JQ° A ητ /ХлЗНЭ _ν Λνη / 2 οΆ О 3-[(lS,2S)-l-[5 -(2-ethyl3-methylpyridin-4-yl)2-[2-(4-fluoro-3,5dimethylphenyl)-3-[3[4-( 1 - hydroxy-2-methylpropan-2-yl) oxy-3-methoxyphenyl]2-oxoimid az o l-1 -yl] 6,7-dihydro-4Hpyrazolo[4,3-c]pyridine 5 -carbonyl] indol-1 yl] -2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-3 1.17 922 ([M+H] ⁺ ) 103 N u „A A Xi yA 3-[(18.28)-1-[5-(2-ethyl3 -methylpyridin-4-yl)2-[2-(3-fluoro-5methylphenyl)-3 -(3 isoquinoline 6-yl-2- oxoimidazol-1 -yl)6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl]indol-1-yl]2-methylcyclopropyl]4H-1, 2,4-oxadiazol-5one SMDTFA05-3 0.96 841 ([M+H] ⁺ ) 104 Αγγ A δ 3-[(lS,2S)-l-[2-[2-(4chlor or-3,5 dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1 -yl]- 6,7-dihydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]5-(2-ethyl-3methylpyridin-4yl)indol-1 -yl]-2methylcyclopropyl]4H-1,2,4-oxadiazol-5one SMDTFA05-3 1.20 875 ([M+H] ⁺ )

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105 nrV ν-ν 9 ΑΙΑ ^/λ^Ο Ν^ ^Η / 0-¼ 0 3-[(lS,2S)-l-[2-[3- [3- (1,3-dimethyl-2oxoquinolin-6-yl)-2oxoimidazol-1-yl]-2(3-methylphenyl)-6,7dihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5-(2-ethyl -3methylpyridin-4yl)indol-1-yl]-2methylcyclopropyl]4H-1,2,4-oxadiazol-5one SMDTFA05-3 1.16 867 ([M+H] ⁺ ) 106 Αν (A / Lo LL ν-ν II II 1 ,ρ ъг o^s^A\/ χΑαο '°Λ 3-[(lS,2S)-l-[2-[2-(2,6dimethylpyridin-4-yl)3-[3-(1-methylindazol5 -yl)-2-oxoimid azol1-yl]-6,7 -dihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5-(2-ethyl-3methylpyridin-4yl)indol-1 -yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMD- TFA05-3 0.86 841 ([M+H] ⁺ ) 107 y , /-0 γ^ΧΑχ^Ο w-h Ή A1 Γ GL^AAD Ο^γΑ \_/ /α ^ν λ^Π ^ν Ανη °Α _ο 3-[(lS,2S)-l-[5-(2,3- dimethylpyridin-4-yl)2-[2-(4-fluoro-3,5- dimethylphenyl)-3-[3-(1 methyl-2-oxoquinolin6-yl)-2-oxoimidazol1-yl]-6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5- carbonyl]indol-1 -yl]2-methylcyclopropyl]4H-1,2,4-oxadiazol-5one SMDTFA05-3 1.09 871 ([M+H] ⁺ ) 108 ρ—/Л /=ι ΛΑ AAnjAJ A·' ³ <Al ХУ Α'' ^Ν χΧ*—C ^N _ν Λνη οΑ _ο 3-[(lS,2S)-l-[2-[2-(2fluoro-3-methylphenyl)-3 [3-[1-(2- methoxyethyl)indazol-5-yl]-2-oxoimidazol-1yl]-6,7-d ihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5-(2-methoxy-3methylpyridin-4yl)indol-1 -yl ] -2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-3 1.38 890 ([M+H] ⁺ )

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109 I-$ 3-[(lS,2S)-l-[2-[2-(4- fluorine-3.5- dimethylphenyl)-3-[3-(4fluoro-1-methylindazol-5 yl)-2-oxoimidazol-1 yl]-6,7-d ihydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]5 -(oxan-4-yl)in ol-1 yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-1 1.34 841 ([M+H] ⁺ ) 110 X, Г\ AX Г> AT HN Z y° 0 3-[(lS,2S)-l-[2-[2-(4- fluoro-3,5dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1 - yl]- 6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5 -(2-methylpyrazol-3 yl)indol-1 -yl]-2methylcyclopropyl] -4H -1,2,4-oxadiazol-5- He SMDTFA05-3 1.30 820 ([M+H] ⁺ ) 111 XX =n xx r\ LX Г ^Cl / nX ^h M _Ol 3-[(18.28)-1-[5-(3-chloro2-methylpyridin-4-yl)2-[2-(4-fluoro-3,5- dimethylphenyl)-3-[3[1-(2- methoxyethyl)ind azol-5 yl]-2-oxoimid azol-1 yl]-6,7-d ihydro-4Hpyrazolo[4,3c]pyridine-5- carbonyl]indol-1-yl]2-methylcyclopropyl]4H-1,2,4-oxadiazol-5one SMDTFA05-3 1.24 908 ([M+H] ⁺ ) 112 Az u c>=V I 3-[(lS,2S)-l-[2-[2-(3,5dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1 -yl]6,7-dihydro-4Hpyrazolo[ 4,3c]pyridin-5-carbonyl]5 -(2-ethylpyridin-4yl)indol-1 -yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDFA05-3 0.95 826 ([M+H] ⁺ )

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FROM v F those ' >about Vyt 1 X X/ bonds S( about A Anh 4 3-[(lS,2S)-l-[2-[2-(4- φτορ-3.5- dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1-yl]6,7-dihydro-4H- pyrazolo[4,3- c]pyridine-5-carbonyl]5-(5- oxaspiro[3,5] nonan-8-yl)indol-1-yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-2 1.47 863 ([M+H] ⁺ ) 114 Q d Λ ⁽ >° ύ '—' o 3-[(lS,2S)-l-[2-[2-(3,5- dimethylphenyl)-3-[3(oxan-4-yl)-2oxoimidazol-1 -yl]-6,7 dihydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]5-(2-ethyl-3methylpyridin-4yl)indol-1 -yl]-2methylcyclopropyl]4H-1,2,4-oxadiazol-5one SMDTFA05-3 1.07 795 ([M+H] ⁺ ) 115 oXa VX To^Ν^θ_θ mC ⁰ A 3-[(lS,2S)-l-[2-[2-(3,5dimethylphenyl)-6methyl-3-[3-(1- methylindazol-5-yl)-2oxoimidazol-1 - yl]- 6,7-dihydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]5-(2-ethyl-3methylpyridin-4yl)indol-1 -yl]-2methylcyclopropyl]4H-1,2,4-oxadiazol-5one SMDTFA05-3 1.17 854 ([M+H] ⁺ ) 116 U- ./ O _ / N-Ν and γ\ _Ν ^Ζ χχ^ΧΥ'ΧΧχ %ν·, OyA d _? 1kGL_Ao L ⁿ OAq 3-[(lS,2S)-l-[2-[(4S)-2- (4-fluoro-3,5dimethylphenyl)-4methyl-3- [3-(1- methylindazol-5-yl)-2oxoimidazol-1 -yl]6,7-dihydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]5 -(oxan-4 -yl)ind ol-1 yl]- 2- methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-2 1.39 837 ([M+H] ⁺ )

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117 ABOUT $ O 3-[(lS,2S)-l-[2-[(4S)-2(4-fluoro-3,5- dimethylphenyl)-3-[3[1-(2- hydroxyethyl)indazol5-yl]-2-oxoimidazol1 -yl]-4-methyl-6,7 dihydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]5 -(oxan-4-yl)in ol 1 yl]-2methylcyclopropyl]4H-1,2,4-oxadiazol-5one SMDTFA05-1 1.27 867 ([M+H] ⁺ ) 118 d Ν—N /=\ / \DDuDDDx /\D~\ S\ ⁰ νΗ ^η 'o—D o 3-[(lS,2S)-l-[2-[(4S)-2- (4-fluoro-3,5dimethylphenyl)-4methyl-3-[3-[4-(oxan-4yl)phenyl]-2- oxoimidazol-1 -yl]6,7-dihydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]5 -(oxan-4-yl)in ol-1 yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-1 1.49 867 ([M+H] ⁺ ) 119 0 \ F X )—( Z'N ^z ^ SD V _N _hl 0 ^V- ^N y x l L Ga A^YSA^ XA ⁰ 4D ^N QAq 3-[(lS,2S)-l-[2-[(4S)-3- [3- [1-[(3S)-1- acetylpyrrolidin-3 yl]indazol-5-yl]-2oxoimidazol -1-yl]-2(4-fluoro-3,5dimethylphenyl)-4methyl-6,7-d ihydro-4Hpyrazolo[4,3c]pyridine-5-carbonyl ]5 -(oxan-4-yl)in ol-1 yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-1 1.29 934 ([M+H] ⁺ ) 120 a r ^l Acv DD/ 1 J I \^N ΑΖΑ-Ρ ⁰ D+ O-D o 3-[(lS,2S)-l-[2-[(4S)-2(4-fluoro-3,5dimethylphenyl)-4methyl-3-[3-[1-[2-[4- (oxetan-3-yl) piperazin-1 -yl] ethyl] ind azol-5 -yl] -2oxoimidazol-1 -yl]6,7-dihydro-4Hpyrazolo[4,3-c]pyridine 5 -carbonyl] -5 -(oxan-4yl)indol-1-yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-1 1.08 992 ([M+H] ⁺ )

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121 ο ___________________/_________________ 3-[(lS,2S)-l-[2-[(4S)-2(4-φτορ-3,5dimethylphenyl)-4methyl-3-[3-[3-methyl-4[6-(4-methylpiperazine1 -yl)pyrimidin-4-yl]phenyl]-2oxoimidazol-1 -yl]6,7-dihydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]5 -(oxan-4-yl)in ol-1 yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-1 0.96 973 ([M+H] ⁺ ) 122 Γχ ''' ^Ν ~ \ ⁰ °^ο 3-[(lS,2S)-l-[2-[(4S)-2(4-fluoro-3,5dimethylphenyl)-4methyl-3-[2-oxo-3-[1(2,2,2- trifluoroethyl)indazol-5yl] imidazol-Gyl]-6,7dihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5-(4-oxanyl)indol-1yl]-2methylcyclopropyl] 4H-1,2,4- Oxadiazol-5one SMDTFA05-1 1.45 905 ([M+H] ⁺ ) 123 A Γ\^^Α Αχ ζΖ~Ύ Ν—/ Ν—X gu Υ \=/^ ^ηΥΑΛ'ο νΑ ^η °Α 3-[(lS,2S)-l-[2-[(4S)-2- (4-fluoro-3,5dimethylphenyl)-4methyl-3-[3-(3- methylimidazo[1,5-a]pyridin-7-yl)-2oxoimidazol-1-yl]6,7-dihydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]5-(oxan-4-yl)indol-1yl]-2- methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-1 1.07 837 CM+N] ⁺ )

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124 X _h /bx'^'X ⁰ nXh °A 3-[(lS,2S)-l-[2-[(4S)-2- (4-φτορ-3,5dimethylphenyl)-4methyl-3- [3-(3- methylimidazo[1,5 - a]pyridin-6-yl)-2oxoimidazol-1 -yl]6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5 -(oxan-4-yl)indol-1 yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-1 1.07 837 ([M+H] ⁺ ) 125 n-\UL IF / χ7χ/« ^ζ _ν Ανη 'ο-Χ ο 3-[(lS,2S)-l-[2-[(4S)-3[3-(1,4- dimethylindazol-5-yl)2-oxoimid az ol-1 -yl] 2-(4-fluoro-3,5- dimethylphenyl)-4methyl-6,7-d ihydro-4Hpyrazolo[4,3c]pyridine-5-carbonyl]5 -(oxan-4-yl)in ol-1 yl]-2methylcyclopropyl] 4H-1,2,4- Oxadiazol-5one SMDTFA05-1 1.37 851 ([M+H] ⁺ ) 126 X to cXy^ ο^γΑ L· mАУтк ο ХА \=/ η \—/ νΑ ^η '°Α _ο 3-[(lS,2S)-l-[2-[(4S)-3[3-[1-[2(dimethylamino)ethyl]indazol-5-yl]-2oxoimidazol-1-yl]-2( 4-fluoro-3,5dimethylphenyl)-4methyl-6,7-d ihydro-4Hpyrazolo[4,3c]pyridine-5-carbonyl]- 5-[(4S)-2,2- dimethyloxan-4yl] indol-1 -yl] -2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-1 1.15 922 ([M+H] ⁺ )

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127 v F rU / X _o ^ν ^Ν · Ν—N C | N xOe.....(ί 'Jr ^oC o 3-[(lS,2S)-l-[2-[(4S)-3- [3-(1,4- dimethylindazol-5-yl)2-oxoimid az ol-1 -yl] 2-(4-fluoro-3,5- dimethylphenyl)-4methyl-6,7-d ihydro-4Hpyrazolo[4,3c]pyridine-5-carbonyl]- 5-[(4S)-2,2- dimethyloxan-4 yl] indol-1 -yl] -2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-1 1.44 879 ([M+H] ⁺ ) 128 y-h 1 L £/ L· ... ^N ~# 4—N 0 '°A 3-[(lS,2S)-l-[5-(2,2- dimethylmorpholin-4yl)-2-[(48)-2-(4-fluoro3,5-dimethylphenyl)-3 [3-(4-fluoro-1- methylindazol-5-yl)-2oxoimidazol-1-yl]-4methyl-6,7-d and hydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]indol-1-yl]-2methylcyclopropyl]4H-1,2,4-oxadiazol-5one SMDTFA05-1 1.30 884 ([M+H] ⁺ ) 129 , F ΛΑ_ _K /O _r <s ^; \_N street N VM ⁰ nXAA^o ΛΛνη f ⁰ Yu 3-[(18.28)-1-[6-fluoro-2[(48)-2-(4-fluoro-3,5dimethylphenyl)-4methyl-3-[3-(1methylindazol-5-yl)-2oxoimidazole -1 -yl]6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5-(oxan-4-yl)indol-1 yl]-2methylcyclopropyl]4H-1,2,4-oxadiazol- 5on SMDTFA05-1 1.38 855 ([M+H] ⁺ ) 130 v F F o^SO. —/ ⁴ 0 οΛ _ο 3-[(18.28)-1-[3-fluoro-2[(48)-2-(4-fluoro-3,5dimethylphenyl)-4methyl-3-[3-(1- methylindazol -5-yl)-2oxoimidazol-1 -yl]6,7-dihydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]5-(oxan-4-yl)indol-1 yl]-2methylcyclopropyl]4H-1,2,4-oxadiazol-5one SMDTFA05-1 1.40 855 ([M+H] ⁺ )

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131 , F lХ— ./0 γ^Ύ y l AmХ1> γΎ \ /—/ ⁴ ο <>ΝΗ °Α 3-[(18.28)-1-[4-φτορ-2[(48)-2-(4-φτορ-3,5dimethylphenyl)-4methyl-3 - [3-(1methylindazol -5-yl)-2oxoimidazole -1 -yl]6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5 -(oxan-4-yl)in ol-1 yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazole -5on SMD- TFA05-1 1.38 855 ([M+H] ⁺ ) 132 XA n-Ν « / ΊΥ XYnAAJYn νΗ ^η οΑ _ο 3-[1-[2-[2-(4-fluoro-3,5- dimethylphenyl)-3-[3-[1(2- methoxyethyl)indazol-5 yl]-2-oxoimid azol-1 yl]-6,7-d ihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5 -(oxan-4-yl)in ol-1 yl ] cyclopropyl] -4H1,2,4-oxadiazol-5-one SMDTFA05-2 1.28 853 ([M+H] ⁺ ) 133 X , / 0 k/ Ν-Ν II G UD ^-θΑΛ/ O^ArY\ ^U0_0) Lu οΑ _ο 3-[1-[2-[2-(4-fluoro-3,5- dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1 -yl]-6,7 dihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5 -(oxan-4-yl)ind ol-1 yl] cyclopropyl] -4H1,2,4-oxadiazol-5-one SMD- TFA05-2 1.26 809 ([M+H] ⁺ ) 134 YW· 'a 3-[[2-[2-(4-fluoro-3,5dimethylphenylyl)-3-[3(1-methylindazol-5-yl)2-oxoimidaz ol-1 -yl] 6,7-dihydro-4H- pyrazolo[4,3c]pyridin-5-carbonyl]5 -(oxan-4-yl)in ol-1 yl]methyl]-4H-1,2,4oxadiazol-5-one SMDTFA05-2 1.18 783 ([M+H] ⁺ )

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135 ³ δ 3-[(lS,2S)-l-[2-[2-(4- φτορ-3,5dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1 - yl]- 6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5 -(oxan-4-yl)in ol-1 yl] -2-(methoxymethyl) cyclopropyl]- 4H- 1,2,4-oxadiazol-5-one SMDTFA05-2 1.30 853 ([M+H] ⁺ ) 136 , F ΖΧ— I/O NN 11 Г Г _N ^0<S rV^ o ^N cAo HO^ 3-[(lS,2R)-l-[2-[2-(4- fluorine-3.5- dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1 - yl]- 6,7-dihydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]5 -(oxan-4-yl)indol-1yl]-2-(morpholin-4ylmethyl) cyclopropyl]-4H-1,2,4oxadiazol-5-one; formic acid SMDTFA05-1 1.04 908 ([M+H] ⁺ ) 137 / Q QV-N r\ 1dГ>'ХуЛ'-у L ⁰ N^ ^H °A 3-[(2S, 3R)-l-[2-[2-(4- fluorine-3.5- dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1 - yl]- 6,7-dihydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]5 -(oxan-4-yl)in ol-1yl]-2,3- dimethylcyclopropyl] 4H -1,2,4-oxadiazol-5one SMDTFA05-2 1.39 837 CM+N] ⁺ ) 138 N/ Qi „ Q ?QX θ ft z 3-[(lR,2S)-l-[2-[[2-(4- fluoro-3,5dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1 yl]-6,7dihydro-4Hpyrazolo[4,3c]pyridin-5-yl]sulfonyl]-5-(oxan- 4yl)indol-1 -yl] -2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-1 1.28 859 ([M+H] ⁺ )

- 102 044109

139 u.,1 °=\ Jl O ° Vji J /=( 3-[(1Κ)-1-[2-[2-(4-φτορ3,5 -dimethylphenyl)-3 [3 -(1 -methylindazol-5 yl)-2-oxoimidazol-1 yl] -6,7 -d ihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5 -(oxan-4-yl)in ol-1 yl]ethyl]-4H-1,2,4- Oxadiazol-5-one SMDTFA05-2 1.28 797 ([M+H] ⁺ ) 140 ΛΧ— ./=0 r^^XN // V KAHL XT оХ^ч ^=0 ^- < ^N xZ^vX X 4-[2-[2-(3.5- dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1 -yl]6,7-dihydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]5-(2-ethyl-3methylpyridin-4yl)indol-1 -yl]-2,2dimethylbutane acid SMDFA05-3 0.90 816 ([M+H] ⁺ ) 141 Zx_ / ⁷ 0 ri^X^N ШЛ Sr ⁰ yXXX °y OH 3-[2-[2-(3.5- dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1 -yl]6,7-dihydro-4Hpyrazolo[4,3-c] pyridin-5-carbonyl]-5(2-ethyl-3 methylpyridin-4yl)indol-1-yl]propanoic acid SMDTFA05-3 1.02 774 ([M+H] ⁺ ) 142 , F H_ nn /=\ Μ ° Ζ^Ο HO ^υ 2-[2-[2-(4-fluoro-3,5dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1 -yl]- 6,7-dihydro-4H- pyrazolo[4,3-c] pyridin-5-carbonyl]-5(oxan-4-yl)indol-1 yl]acetic acid SMDTFA05-2 1.21 743 ([M+H] ⁺ )

- 103 044109

143 \—/ / Η Λ X GL ΑΧ) ^Ζ _Ο Ή° ^Η (lS,2S)-l-[2-[2-(3,5- dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1 -yl]-6,7 dihydro-4Hpyrazolo[4,3- c]pyridin-5-carbonyl]5-(2-ethyl-3methylpyridin-4yl)indol-1 -yl]-2methylcyclopropan-1 carboxylic acid SMDTFA05-3 1.08 800 ([M+H] ⁺ ) 144 8 2 \--/ _ο τ 1-[2-(4-fluoro-3,5- dimethylphenyl)-5-[5(oxan-4-yl)-1 -(1H1,2,4-triazol-5- ylmethyl)indole-2 - carbonyl]-6,7-dihydro4H-pyrazolo[4,3 - c]pyr idin-3 -yl]-3 -(1 methylindazol-5yl)imidazol-2-one SMDTFA05-1 1,Yu 766 ([M+H] ⁺ ) 145 8 2 b ^{ 1-[2-(4-fluoro-3,5- dimethylphenyl)-5 - [ 1 [(18,28)-2-methyl-1-(5sulfanylidene-4H- 1,2,4-oxadiazole 3- yl)cyclopropyl]-5(oxan-4-yl)indol-2carbonyl]-6,7-dihydro- 4H-pyrazolo[4,3c]pyridin-3-yl]-3-(1 methylindazol-5yl)imidazol-2-one SMDTFA05-2 1.45 839 ([M+H] ⁺ ) 146 N-Ν /=\ /=< I ¹ A ⁰ Zk'^'x ( ⁰ _ν Λνη Ύ 3-[(lS,2S)-l-[2-[2-(4- fluoro-3,5dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazol-1-yl]- 6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5 -(oxan-4-yl)in ol-1 yl]-2methylcyclopropyl] 4H-1,2,4-thiadiazol-5-one SMDTFA05-2 1.46 839 ([M+H] ⁺ )

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147 nn /=\ /=\ Ν Μ ° X ,Ν-</“Λ_Λ% _μ Χνη Ν 1 ν^ν 1-[2-(4-φτορ-3,5dimethylphenyl)-5-[1[(18.28)-2-methyl-1-(1Htetrazol-5yl)cyclopropyl]-5 (oxan-4-yl)indol- 2carbonyl]-6,7-dihydro4H-pyrazolo[4,3 c]pyr idin-3 -yl]-3 -(1 methylindazol-5yl)imidazol-2-one SMDTFA05-2 1.26 807 ([M+H] ⁺ ) 148 8 $Α|>Ρ (18.28)-1-[2-[2-(4-fluoro3,5-dimethylphenyl)-3 [3 -(1-methylindazol-5 yl)-2-oxoimidazol-1 yl]- 6,7- dihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5 -(oxan-4-yl)in ol-1 yl]-2-methyl-Mmethylsulfonylcyclopane-1-carboxylic acid SMDTFA05-1 1.31 860 ([M+H] ⁺ ) 149 VF XX— \=/ /=Ν Ν-Ν 9 LLo jO νΓ ^η ·οΑ _ο 3-[(lS,2S)-l-[2-[[(4S)-2- (4-fluoro-3,5dimethylphenyl)-4methyl-3-[3-(1- methylindazol-5-yl)-2oxoimidazol-1-yl]6,7-dihydro-4Hpyrazolo[4,3- c]pyridin-5-yl]methyl]5 -(oxan-4-yl)in ol-1 yl]-2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-2 1.17 823 ([M+H] ⁺ ) 150 Ν—Ν / \ [ ] J 1 II °^Ύ ίΥ ⁴ Ν—/ '7'^u-on O 2-[2-[3- [3- (cyclohexylmethyl)-2oxoimidazolidin-1 yl]-2-phenyl-6,7dihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5-(2,3-d imethylpyridin4-yl)indol-1 -yl]-2methylpropane acid SMDTFA05-3 1.13 714 ([M+H] ⁺ )

- 105 044109

151 o χχό UATT] 7 n /VN ^N J^° 3-[2-[2-[3- [3- (cyclohexylmethyl)-2oxoimidazolidin-1 yl]-2-phenyl-6,7dihydro-4Hpyrazolo[4,3c]pyridin-5 - carbonyl]-5-(2,3 dimethylpyridin-4yl)indol-1-yl]propan- 2-yl]-4H-1,2,4- Oxadiazol-5-one SMDTFA05-3 1,Yu 755 ([M+H] ⁺ ) 152 Ar Q X U A Ada 3-[(lS,2S)-l-[2-[3- [3- (2,2-dimethylpropyl)-2oxoimidazolidin-1yl]-2-phenyl-6,7dihydro-4Hpyrazolo[4,3c]pyridin-5-carbonyl]5-(2-ethyl-3methylpyridin-4yl)indol-1 -yl ] -2methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-3 1,I 754 ([M+H] ⁺ ) 153 , F AC_ =N WW ^N - Y ^N \ 1 XI o^X^x. _ kADL—ex n.Ah P oAq 3-[(18.28)-1-[5-(2-ethyl3-methylpyridin-4-yl)2-[2-(4-fluoro-3,5dimethylphenyl)-3-[3-(1methylindazol-5- yl)-2oxoimidazolidin-1 yl]-6,7-d ihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl]indol-1-yl]2-methylcyclopropyl]4H-1,2,4-oxadiazol-5one SMDTFA05-3 1.15 860 ([M+HD 154 Xx— f= ^N \ Wn ZV ^N ^ NN f J o/a _ kn xA ^- C3 ^N X^NH O oAq 3-[(lS,2S)-l-[2-[2-(3,5dimethylphenyl)-3-[3-(4imidazol-1 -ylphenyl)2-oxoimidazolidin-1 yl]-6, 7-dihydro-4Hpyrazolo [4,3c]pyridin-5-carbonyl]5-(2-ethyl-3methylpyridin-4yl)indol-1 -yl]-2methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMDTFA05-1 0.86 854 ([M+H] ⁺ )

- 106 044109

155 NN 9 Ji Τ/Ν nN Of ¹ N^H /) ⁰ X 3-[(lS,2S)-l-[2-[2-(3,5dimethylphenyl)-3-[3-(1methylindazol-5-yl)-2oxoimidazolidin-1 yl]-6, 7-dihydro-4Hpyrazolo[ 4,3c]pyridin-5-carbonyl]5-(2-ethyl-3methylpyridin-4yl)indol-1 -yl]-2methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one SMDTFA05-3 1.14 842 ([M+H] ⁺ ) 156 by ^N NN O^NJ \/— n^nh ° ⁴ o 3-[(lS,2S)-l-[2-[2-(3,5dimethylphenyl)-3 -(5imide azol-1 -yl-3-oxo1H-isoindol-2-yl)-6,7dihydro-4Hpyrazolo[ 4,3c]pyridin-5-carbonyl]5-(2-ethyl-3methylpyridin-4yl)indol-1 -yl]-2methylcyclopropyl]4H-1,2,4-oxadiazol-5one SMDFA05-3 0.79 825 ([M+H] ⁺ ) 157 A. n\n nn AY AO ^- A ^{n 0} Yu 3-[(lS,2S)-l-[2-[2-(3,5dimethylphenyl)-3-[M, 3dimethyl-4-(3-propan-2yl-1,2,4 triazol-4-yl) anilino]-6,7-dihydro4H-pyrazolo[4,3 c]pyridin-5-carbonyl]5-(2-ethyl-3methylpyridin-4yl)indol 1-yl]-2- methylcyclopropyl] 4H-1,2,4-oxadiazol-5one SMDTFA05-3 1,Yu 856 ([M+H] ⁺ ) 158 dhaH <V\ yvQy-bf °A 3-[(18.28)-1-[5-(2-ethyl3 -methylpyridin-4-yl)2-[2-(4-fluoro-3,5d and methyl phenyl)-3 - [Nmethyl-4- (2-propan-2ylimidazol-1 -yl) anilino]-6,7-dihydro4H-pyrazolo[4,3 c]pyridin-5carbonyl] indol-1 -yl]-2 -methylcyclopropyl]4H-1,2,4- Oxadiazol-5one SMDTFA05-3 1.05 859 ([M+H] ⁺ ) 159 , F Z4— —( )=/ )=N NN (Χ,Ν m ΧΛνΑλ 1 1 Η ^N^ ⁰ ΑΛ” /\,N -ΛΑ—ΛΆι n^nh ⁰ yu 3-[(18.28)-1-[5-(2-ethyl3-methylpyridin-4-yl)2-[2-(4-fluoro-3,5dimethylphenyl)-3 - [4-(3 propan-2 -yl-1,2,4triazol-4-yl) anilino]6,7-dihydro-4Hpyrazolo[4,3c]pyridin-5carbonyl]indol-1 -yl]2-methylcyclopropyl]4H-1,2,4-oxadiazole -5on SMDFA05-3 0.91 846 ([M+H] ⁺ )

Example 160. Preparation of a crystal of monosodium salt hydrate of compound 1.

To that obtained in example 1 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3 ,5dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4Hpyrazolo [4,3-c] pyridin-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound 1, 1005.5 mg) was added with acetonitrile (3.02 ml) to dissolve connections at room temperature. 5M sodium hydroxide aqueous solution (0.495 ml) and sodium hydrate seed crystals of Compound 1 were added to the solution, and the mixture was stirred at room temperature for

- 107 044109 2 hours. Tert-butyl methyl ether (3.02 ml) was also added and the mixture was stirred at room temperature for 1 hour, and then tert-butyl methyl ether (9.05 ml) was added and the mixture was stirred at room temperature for for 2 hours to obtain sodium hydrate crystals of the title compound (1007.0 mg) in the form of powdery crystals (sample 160a). It should be noted that the seed crystals were obtained using the following method. DMSO (0.244 ml) and 2M sodium hydroxide aqueous solution (0.032 ml) were added to compound 1 (26.9 mg). This solution (0.030 ml) was sublimated at -20°C for 2 days. Acetonitrile (0.015 ml) was added to the resulting freeze-dried product and the mixture was stirred at room temperature for 2 days, and then tert-butyl methyl ether (0.015 ml) was added and the mixture was stirred at room temperature for 12 days to obtain sodium hydrate crystals. salts of compound 1 in the form of powdered crystals (sample 160b).

Example 161 Preparation of a crystal of the compound of Example 66.

3-[(1S,2s)-1-[5-[(4s)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -4-methyl-3-[3-(1methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indole -1yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (Example 66, 400.3 mg) was suspended in ethanol (8.00 ml) to which the seeds of Example 66 were added and the mixture was stirred at 70°C for 5 minutes. After stirring the suspension at 50°C for 1 hour, it was stirred for 17 hours at room temperature to obtain crystals (381.1 mg) of the compound of Example 66 as powdery crystals (sample 161a). It should be noted that the seed crystals were obtained using the following method.

Preparation Example 66 (31.8 mg) was suspended in ethanol (0.636 ml) and stirred at 80°C. After stirring the suspension at 40°C for 1 hour, it was stirred at room temperature for 22 hours to obtain crystals (24.2 mg) of the compound of Example 66 as powdery crystals (sample 161b).

Example 162. Preparation of the hemicalcium salt hydrate crystal of the compound of Example 67.

Ethanol (5.60 ml) and 2M aqueous sodium hydroxide (0.75 ml) were added to 3-[(1S,2S)-1-[5[(4S)-2,2-dimethyloxan-4-yl]- 2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2oxoimidazol-1-yl]-4-methyl -6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (compound of example 67 , 1120 mg), and the compound was dissolved at room temperature. 1.26M calcium acetate aqueous solution (0.68 ml), calcium salt hydrate seeds of Example 67 and water (0.68 ml) were added to the solution, and the mixture was stirred at room temperature for 3 hours. Then water (1 .2 ml) and the mixture was stirred at room temperature for 1 hour, and then water (2.3 ml) was added and the mixture was stirred at room temperature for 1 hour to obtain calcium salt hydrate crystals (973.0 mg) of Example 67 in the form of powdery crystals (sample 162a). It should be noted that the seed crystals were obtained using the following method.

The compound of Example 67 (69.0 mg) was dissolved in DMSO (0.229 ml) and 1.06 M calcium methoxyethoxide (0.147 ml) was added. This solution (0.015 ml) was sublimated at -20°C for 2 days. To the resulting freeze-dried product, water-acetonitrile (3:1, 0.015 ml) was added, and the mixture was stirred by shaking at room temperature for 7 days to obtain calcium salt hydrate crystals of the compound of Example 67 as powdery crystals (Sample 162b).

Example 163. Powder X-ray diffractometry.

Sodium salt hydrate crystals (samples 160a and 160b) of compound 1, obtained in example 160, crystals (samples 161a and 161b) of example 66, obtained in example 161, calcium salt hydrate crystals (samples 162a and 162b) of example compound 67, obtained in Example 162, each was subjected to X-ray powder diffraction measurements using the following measurement techniques. The results are shown in Fig. 1-6.

Measuring instrument: D8 Discover with GADDS CS diffractometer (Bruker AXS).

Anode: Cu.

Voltage: 40 kV Current: 40 Ma.

Scan range: 5-25.3°.

Step width: 0.02°.

Example 164 Thermogravimetric analysis/differential thermal analysis.

The sodium salt hydrate crystals of Compound 1 (sample 160a) and the calcium salt hydrate crystals of Compound Example 67 (sample 162a) were each subjected to thermogravimetric analysis/differential thermal analysis using the following measurement method. The results are shown in FIG. 7 and 8. It should be noted that sample 160a was dehydrated at approximately 110°C and no clear melting point was determined. In addition, sample 162a was dehydrated at approximately 240° C. and no clear melting point was determined.

Measuring device: EXSTAR TG/DTA6200R (Seiko Instruments Inc. (Current company name: Hitachi High-Tech Science Corporation)).

- 108 044109

Measuring range: 30-350°C.

Heating rate: 10°C/min.

Atmosphere: nitrogen.

Example 165. Determination of water using the Karl Fischer method.

The water content of the sodium salt hydrate crystal of Compound 1 (sample 160a) and the calcium salt hydrate crystal (sample 162a) of Example 67 was measured using a Karl Fischer coulometric moisture meter (Metrohm, 756 KF Coulometer). The result was 7.4% for sample 160a and 6.2% for sample 162a. From the results of Example 164 and Example 165, it was confirmed that the water contained in the sodium salt hydrate crystals of Compound 1 and the calcium salt hydrate crystals of Example 67 was mainly crystalline water.

Test Example 1. In vitro measurement of cAMP signal activation of the junction in human GLP1R.

Peptide.

Human GLP-1 (7-37) was obtained from PEPTIDE INSTITUTE, INC., and was dissolved in phosphate buffered saline to 200 μM, then stored in a freezer at -80°C. Cell culture.

A stably expressing human GLP1R cell line (hGLP1R-HEK293) was used in the experiment. Cells were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (Sigma-Aldrich), 100 units/ml penicillin G and 100 μg/ml streptomycin sulfate (Gibco), and 500 μg/ml geneticin (Gibco ), in a humid atmosphere containing 5% CO ₂ at 37°C. cAMP-based assay.

hGLP1R-HEK293 was seeded in 96-well plates at 2.0 x 104 cells per well and cultured overnight. The next day, the cell culture medium was changed to 50 μl of medium A (DMEM, 20 mM HEPES, 0.05% BSA, 0.5 mM 3-isobutyl-1-methylxanthine) and the cells were incubated at 37°C for 30 min. Then, 50 μl of medium B (DMEM, 20 mM HEPES, 0.05% BSA, 0.5 mM 3-isobutyl-1methylxanthine) containing GLP-1 or compound was added and the cells were incubated at 37°C for an additional 30 min. Then, 100 μl of lysis assay buffer (Applied Bioscience) was added and the cells were incubated at 37°C for 30 min. The cAMP concentration was quantified using the HiRange cAMP kit (Cisbio Bioassays). Calculation of EC ₅₀ .

Having established the cAMP concentration when human GLP-1(7-37) was driven from 1 nM to 100%, the cAMP concentration in each well was converted to reaction rate (%). Using four-variable logistic regression analysis performed by XLfit (version 5.4.0.8), dose response curves were generated for each example compound and half maximum (50%) effective concentrations (EC ₅₀ ) were calculated. The results are shown in table. 3.

- 109 044109

EC50 of each example compound

Table 3

Example No. EC50 (nM) 1 8.8 2 5.6 3 6.1 4 12 5 6.1 6 2.9 7 3.2 8 2.5 9 1.8 10 2.8 AND 1.1 12 2.7 13 3.7 14 2.3 15 2.2 16 0.51 17 1.0 18 1.3 19 1.3 20 1.9 21 1.6 22 2.3 23 1.8 24 2.5 25 4.0 26 0.77 27 2.3

Example No. EC50 (nM) 28 1.9 29 1.4 thirty 1.4 31 0.74 32 0.94 33 1.6 34 h,o 35 3.2 36 2.1 37 2.5 38 1.7 39 1.0 40 2.2 41 2.4 42 1.9 43 1.5 44 1.5 45 1.6 46 3.3 47 2.0 48 h,o 49 3.8 50 2.9 51 8.7 52 6.7 53 2.9 54 3.9

Example No. EC50 (nM) 55 3.7 56 3.4 57 8.1 58 7.6 59 1.5 60 4.9 61 1.6 62 1.1 63 1.1 64 2.0 65 3.5 66 0.81 67 1.2 68 1.8 69 2.8 70 1.5 71 1.3 72 2.3 73 2.5 74 6.2 75 6.2 76 2.4 77 1.4 78 3.6 79 2.4 80 2.4

Test example 2. Stimulating effect on insulin secretion and reducing blood glucose levels.

A solution of compound Example 67 (solvent composition: PEG400 (10% v/v): propylene glycol (10% v/v): 100 mM glycine-NaOH buffer, pH 9.0 (80% v/v)) was administered intravenously to an anesthetized male cynomolgus monkey continuously. for 40 minutes, and reached a steady-state plasma drug concentration of 0.94, 1.6 or 4.8 nmol/l. Exenatide solution (solvent: Tween 0.05%/PBS(-)), which is the control drug, was administered in the same manner and a steady-state plasma drug concentration of 9.2 or 23.9 pmol/L was achieved. The vehicle control group was administered the vehicle of the compound of Example 67. Then, a 50% glucose solution was administered intravenously (the weight of glucose administered to the macaque is: 0.5 g/kg) and a blood sample was collected every 5 or 10 minutes to measure the concentration of insulin and plasma glucose. The area under the curve was calculated by determining the time dependence of each parameter after drug administration to evaluate the stimulating effect on insulin secretion and lowering blood glucose levels.

In the group administered the compound of Example 67, an increase in the area under the insulin curve (Fig. 9) and a decrease in the area under the plasma glucose curve (Fig. 10) in a dose-dependent manner was observed at steady-state plasma concentrations from 0.94 to 4.8 nmol /l. A similar increase in the area under the insulin curve (Fig. 9) and a decrease in the area under the plasma glucose curve (Fig. 10) were observed in the group receiving exenatide (control drug) at steady-state plasma concentrations from 9.2 to 23.9 pmol /l with continuous intravenous administration. It should be noted that the concentration of 9.2 pmol/L (38.5 pg/ml) of exenatide was close to the lower limit of the therapeutic concentration range (50-350 pg/ml) of exenatide in diabetic people (drug administration form - 110 044109 , Byeta subcutaneous injection 5 mcg pen 300, Byeta subcutaneous injection 10 mcg pen 300, September 2016 (revised version 9)). This result indicates that the compound of Example 67 exhibits a stimulating effect on insulin secretion and lowering blood glucose levels equivalent to exenatide at plasma concentrations of 1.6 nmol/L or higher.

Test example 3. Anorexigenic effect.

The compound of Example 67 was orally administered to a male cynomolgus monkey for 5 consecutive days, and its effect on food intake for 90 minutes was assessed each day 3 hours after administration. Exenatide, a control drug, was administered subcutaneously for 5 consecutive days in the same manner, and its effect on food intake for 90 min was assessed 30 min after administration. The vehicle control group was administered both oral diluents of Example 67 (DMSO (10% v/v): Cremophor EL (10% v/v): PEG 400 (15% v/v): 100 mM glycine-NaOH buffer pH 10 (65% vol.), 1 ml/kg) and exenatide subcutaneous vehicle (0.05% w/v Tween/PBS (-), 0.1 ml/kg). At the same time, the subcutaneous administration vehicle was further administered to the group receiving the compound of Example 67 (drug administration concentration, 0.05 or 0.1 mg/ml), and the oral administration vehicle was additionally administered to the exenatide group (drug administration concentration , 3 or 6 µg/ml).

Example 67 reduced food intake in a dose-dependent manner (FIG. 11A). The degree of suppression was almost equivalent to the control drug exenatide (Fig. 11B). Plasma drug concentrations (mean ± standard error) immediately after measuring food intake in each group were 8.0 ± 1.0 nM (0.05 mg/kg group) and 16.3 ± 2.3 nM (0.1 mg/kg group). mg/kg) for the group receiving the compound of Example 67, and 91 ± 8.5 pM (0.3 μg/kg group) and 199 ± 13.1 pM (0.6 μg/kg group) in the exenatide group.

Test case 4. Pharmacokinetics of compounds.

Following oral administration (gavage using a gastric catheter) of a suspension of calcium salt hydrate crystals (sample 162a) (dosage: 0.05, 0.15, 0.45 and 1.35 mg/kg) prepared from the compound of Example 67 obtained in Example 162, a male cynomolgus monkey (n=2 for each dose) had venous blood collected sequentially to obtain plasma. Plasma drug concentrations were determined by liquid chromatography tandem mass spectrometry. The lower limit of quantitation was 0.3 ng/ml. The plasma concentration time course for the drug is shown in FIG. 12, and the time to reach maximum plasma drug concentration ( _Tmax ), maximum plasma drug concentration ( _Cmax ) and area under the drug plasma concentration-time curve up to 24 hours after administration (AUC0-24 _hours ) are illustrated in table 4.

At all dosages, plasma drug concentrations reached _Cmax 2 hours after oral administration and then decreased in a similar time-dependent manner. The increase in the content of the drug in the blood plasma at dosages of 0.05, 0.15, 0.45 and 1.35 mg/kg (dose ratio: 1:3:9:27) was almost proportional to the increase in dosage ( _Cmax ratio: 1 ,0:4.3:6.7:31, AUC0-24h _ratio : 1.0:5.7:8.8:44). It has been shown that this substance is absorbed and excreted through the intestinal tract in a dose-proportional manner.

Table 4

_Tmax , Cmax and AUC0-24 _hours after oral administration of this substance to a male cynomolgus monkey

Dose (mg/kg) (Sshupyushenne) | Τ^χ (h) (ng/ml) Smack j (Ratio) AUG (ng-h/ml) 0-24 H (Ratio) 0.05 1.0 2.0 4.78 1.0 23.7 1.0 0.15 3.0 2.0 20.7 4.3 135 5.7 0.45 9.0 2.0 32.0 6.7 208 8.8 1.35 27 2.0 148 31 1040 44

Claims (6)

1. Compound formula its salt or solvate of either a compound or a salt of a compound. 2. A compound according to claim 1, where the compound is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4yl]-2-[(48)-2-( 4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4methyl-6,7-dihydro-4H-pyrazolo [4,3-c]pyridin-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4oxadiazol-5-one or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 1, a salt thereof or a solvate thereof of the following formula: 4. Hemicalcium salt hydrate of the compound according to any one of claims 1-3. 5. A pharmaceutical composition containing a compound according to any one of claims 1 to 4, its salt or solvate or a compound or salts of a compound as an active substance, and an excipient. 6. A method of treating or preventing non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity in a patient in need thereof, the method comprising administering an effective amount of a compound according to any one of claims 1 to 4, a salt or solvate thereof or a compound or a salt of a compound.